JP2003501476A - Antiviral indoleoxoacetylpiperazine derivatives - Google Patents

Abstract

  (57) [Summary] PROBLEM TO BE SOLVED: To provide a drug and a compound having biological activity, pharmaceutical composition and use thereof. These compounds are indo-loxoacetylpiperazine derivatives. [Effects] These compounds are used alone or in combination with other anti-viral agents, anti-infective agents, immunomodulators or HIV entry inhibitors, and have unique antiviral activity, especially therapeutic activity of HIV and AIDS It has.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel compounds with medicinal and biochemical properties, their pharmaceutical compositions and their use. In particular, the present invention relates to indoleoxoacetylpiperazine derivatives. These compounds have unique antiviral activity and can be used alone or in combination with other antiviral, antiinfective, immunomodulatory or HIV entry inhibitors.
More particularly, the invention relates to therapeutic means for HIV and AIDS.

[0002]

[Prior art and its problems]

HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem with an estimated 33.4 million patients worldwide. Currently available HIV groups include 6 nucleoside reverse transcriptase (RT) inhibitors (zidovudine, dedanosine, stapdin, lamivudine, salcitabine and abacover) and 3 non-nucleoside reverse transcriptase (nevirapine, delapine). There are five peptidomimetic protease inhibitors (Saquinaba, Indinavar, Ritonaber, Nelfinavar and Amprenavar), as well as Virdin and Efavirenz). Each of these agents, when used alone, only temporarily arrest viral replication. However, when used in combination, the above agents have a significant effect on disease progression. In fact, it has been reported that the mortality rate of AIDS patients is considerably reduced. Despite these results, ultimately 30-50% of patients also fail to treat combination drugs. Viruses that are susceptible to inadequate pharmacological activity within certain cell types, non-compliance, constrained tissue permeability and drug-specific constraints (eg nucleoside alonag cannot carophosphorylate in the rest of the cell). Has led to imperfections in control.
High replication rates and rapid changes of HIV-1 due to frequent mutations also lead to the development of drug resistant mutants and therapeutic failure when drug concentrations are not optimal. (Larder and Kemp, Gulick, Morris-J
ones, et al., Kurizkes, Vacca and Condra, Schina.
zi et al. and Flexner, Ref. 6-12). As a result, a new anti-HIV drug that exhibits a clear resistance pattern and is excellent in pharmacological activity and safety is also necessary in the sense of broadening the therapeutic selectivity.

The HIV-1 drugs currently on the market are either nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Recently, non-nucleoside reverse transcriptase inhibitors have gained increasing importance in the treatment of HIV infection. At least 30 NNRTIs have been published (DeCler
cq, Ref. 13). Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis (heteroaryl) piperazine derivatives (derabadine) are already approved for clinical use. Also indole-3-sulfone,
Piperazinoindole, piperazinoindole and 5H-indolo [3,2-b
] Some indole derivatives, including [1,5] benzothiazepine derivatives, are HI
It has been reported as a V-1 reverse transcriptase inhibitor (Green.
Lee et al., Ref, 1, Williams et al., Ref. 2, Romero, etc., R
ef. 3, Font et al., Ref. 14, Romero et al., Ref. 15, You
ng et al., Ref. 16, Genin et al. Ref. 17 and Silver
stri et al., Ref. 18). Idol 2-carboxamide also adheres to cells and HI
Reported as an inhibitor of V infection (Boschelli et al., US Pat. No. 5,4.
24,329, Ref. 4). Finally, 3-substituted indole natural products (semicocliogenols A and B, didemethylasteriquinone and isococliodinol).
Has been reported as an inhibitor of HIV-1 protease (Fredenhag
en et al., Ref. 19). However, none of these publications describe or suggest the novel compounds of the invention and their use in inhibiting antiviral infections, including HIV infections.

Structurally close compounds have already been reported (Brewster et al., Ref. 2).
0, Archibald et al., Ref. 21, American Home Pr
Products GB 1126245, Ref. 5). However, they are symmetrical bis (3-indolylglyoxamide) s, which, unlike the asymmetric indoleoxoacetylpiperazine derivatives, clearly differ in chemical structure from the compounds of the present invention, and disclosure for the treatment of antiviral infections. Nor. Surprisingly, the indole group present in the compounds of the present invention was derived from Delavardin (D) commercially available from Upjohn.
ueweke et al., 1992, 1993, Ref. It is common to many non-nucleoside HIV-1 reverse transcriptase inhibitors, including 22 and 23).

The following compounds are commercially available, but their pharmaceutical use, particularly mammalian antiviral use, has not been reported.

Compound LJ952 (Menai Orga, Gwynedd, North Wales)
nics Ltd. Made):

[0007]

[Chemical 7]

[0008] Compound TRI-29586 (manufactured by Tripos):

[0009]

[Chemical 8]

Known publications are listed below. First, the patent documents are listed below: Greenlee, W.M. J. Srinivasan, P .; C. Indole Reverse Transcriptase Inhibitor, US Pat. No. 5,124,327. 2. Williams, T .; M. Ciccarone, T .; M. ; Saari
, W. S. Wai, J .; S. Greenlee, W .; J. Balani,
S. K. Goldman, M .; E. Theohrides, A .; D. , HI
Indole as a V reverse transcriptase inhibitor, European Patent No. 530907. 3. Romero, D. L. Thomas, R .; C. , Production of Substituted Indoles as Anti-AIDS Drugs, PCT WO 93/01181. 4. Boschelli, D.M. H. Connor, D .; T. Unangst
, P .; C. Indole-2-carboxamide as a cell adhesion inhibitor, US Pat. No. 5,424,329. 5. Therapeutic bis (indolyl) compounds. British Patent No. 1126245 (Amer
ican Home Products Corp. ).

The following are general documents: Larder B. A and Kemp S. D. , HIV-1 Reverse Transcriptase Multiple Mutations Confer High Levels of Resistance to Zidovudine, Science, 246: 1155-1158, 1989. 7. Gulick R. M. , Recent Antiretroviral Therapy; Review, Quali
ty of Life Research, 6: 471-474, 1997. 8. Kuritzkes D.M. R. , HIV resistance to recent treatments, Ant
Ivory Therapy, 2 (Supplement 3): 61-67
, 1997. 9. Morris-Jones S, Moyle G and Easterbrook
k P. J. , HIV-1 Infection Antiviral Treatment, Expert Opinio
non Investigative Drugs, 6 (8): 1049.
-1061, 1997. 10. Schinazi R. F, Larder B. A and Mellors
J. W. , Mutation of Drug-Resistant Retrovirus Gene, Internat
Ional Antivial News, 5: 129-142, 1997.
11. Vacca J. P and Condra J. et al. H. , Clinically effective HIV-
1 Protease Inhibitor, Drug Discovery Today, 2:26
1-272, 1997. 12. Flexner D.M. , HIV-Protease Inhibitors, Drug The
rapid, 338: 1281-1292, 1998. 13. De Clercq E. , Role of Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in the Treatment of HIV-1 Infection, Antivir
al Research Vol. 38 pp. 153-179, 1998. 14. Font, M .; Monge, A .; Cuartero, A .; ; Elor
riaga, A .; Martinez-Irujo, J .; J. ; Alberdi
, E. Santiago, E .; Prieto, I .; Lasarte, J .;
J. Sarobe, P .; And Borras, F .; , Indole and Pyrazino [4,5-b] indole Eur. As Nonnucleoside Analog Inhibitors of HIV-1 Reverse Transcriptase. J. Med. Chem. , 30,963-
971, 1995. 15. Romero, D. L. Morge, R .; A. Genin, M .; J.
Biles, C .; Busso, M .; Resnick, L .; ; Altau
s, I.S. W. Reuser, F .; Thomas, R .; C and Tarple
y, W. G. , Bis (heteroaryl) piperazine (BHAP) reverse transcriptase inhibitors; Structure-activity relationships of novel substituted indole analogs and 1
-[(5-Methanesulfonamido-1H-indol-2-yl) -carbonyl] -4- [3- [1-methylethyl) amino] -pyridinyl] piperazine monomethanesulfonate (U-90152S), second generation Clinical Candidates, J. Med. Ch
em. , 36, 1505-1508, 1993. 16. Young, S.M. D. Amblard, M .; C. Britcher,
S. F. Gray, V .; E. Tran, L .; O. Lumma, W .; C. ;
Huff, J .; R. Schleif, W .; A. Emini, E .; E. ; O '
Brien, J .; A. Pettibone, D .; J. , Heterocyclic indole 3-sulfones, B as inhibitors of HIV-reverse transcriptase
ioorg. Med. Chem. Lett, 5, 491-496, 1995. 17. Genin, M .; J. Poel, T .; J. Yagi, Y .; Bile
s, C.I. Althaus, I .; Keiser, B .; J. Kopta, L .;
A. Friis, J .; M. Reuser, F .; Adams, W .; J. ;
Olmsted, R.M. A. Voorman, R .; L. Thomas, R .; C
． And Romero, D .; L. , New bis (heteroaryl) piperazine (BH
AP) Reverse Transcriptase Inhibitor Synthesis and Biological Activity: Structure-Activity Relationships and Increased Metabolic Stability of Novel Substituted Pyridine Analogs, J. Am. Med. Chem
． 39, 5267-5275, 1996. 18. Silvestri, R .; Artico, M .; Bruno, B .; ; M
assa, S .; Novellino, E .; Greco, G .; Marong
iu, M .; E. Pani, A .; De Montis, A and La Coll
a, P. , 5H-Indolo [3 designed as a conformationally restricted analog of the human immunodeficiency virus type 1 reverse transcriptase inhibitor L-737,126.
And physiological evaluation of 2,2-b] [1,5] benzothiazepine derivatives, Anti
virtual Chem. Chemother. , 9, 139-148, 1998
． 19. Fredenhagen, A .; Petersen, F .; ; Tintel
not-Blomley, M .; Rosel, J .; Mett, H and Hug,
P. J. , Inhibitors of HIV-1 protease and EGF-R protein tyrosine kinase related to asteriquinone produced by the bacterium Chrysosporium nadarium, Antibiotics, 50, 395-401, 1997. 20. Brewster, K .; Green, D .; M. Pinder, R .; M
． Thompson, P .; B. J. Antihypertensive 1,4-bis (2-indol-3-ylethyl) piperazine, Antihypertensive 1,4;
-Bis (2-indol-3-ylethyl) piperazines, 21. Archibald, John L. Freed, Meier E .; ，
1,4-bis (2-indol-3-ylethyl) piperazine, J.P. Med. C
hem. , 17, 745-7, 1974. 22. Dueweke T.S. J. Et al., Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Is Mediated by Novel Bisheteroarylpiperazine Binding, J Biol. Chem. Vol. 267 pp 27-30, 1992. 23. Dueweke T.S. J. U-90152, an inhibitor of human immunodeficiency virus replication. Agent. Chemother. Vol. 37 pp1127
-1131, 1993. 24. Gribble, G .; W. , Recent Developments on Methods and Applications of Indole Ring Synthesis, Contemp. Org. Synth, 1, 145-72, 1994. 25. Lingens, F.M. Lange, J .; , 3-Indol-3-ylglycerol and 3- (N-methylindol-3-yl) glycerol synthesis,
Justus Liebigs Ann. Chem. , 738, 46-53, 1
970. 26. Desai, M .; Watsey, J .; W. H. ; Zuckerman
, M .; , 1-Arylpiperazine effective preparation, Org. Prep. Proce
d. Int. , 8, 85-6, 1976. 27. Potts, B.M. J. Mini-reverse transcriptase (RT) assay, Aldovimi, A .; , B. D. Walker (ed.), Technology in HIV Research, Stockton Press, NY. p. 103-106, 1990
． 28. Weislow, O.I. S. R.K. Kiser, D.M. L. Fine, J.M. B
ader, R.A. H. Shoemaker, and Boyd, M .; R. , HIV-1
Novel Soluble Formazan Assay for Cytopathic Effects: Utilization of AIDS Antiviral Activity for High Flux Screening of Synthetic and Natural Products, Journal ofN
national Cancer Institute 81: 577-586.
1989. 29. Johnson, V.D. A. And R.A. E. Byrington, Infection Analysis, A.S. Aldovini and B.I. D. Walker (ed.), HIV research technology, pp. 71-76, Stockton Press, NY. 1990. 30. Harada, S .; , Koyanagi, Y .; And N.N. Yamamoto
, HTLV-III / LA in HTLV-1 bearing cells MT-2 and MT-4
V infection and use in plaque analysis, Science 229: 563-566.
1985. 31. (a) Behun, J. et al. D. Levine, R .; J. Org. Chem
． 1961, 26, 3379. (B) Rossen, K .; Weissman,
S. A. Sager, J .; Reamer, R .; A. Askin, D .; ; V
olante, R.A. P. Reider, P .; J. Asymmetric hydrogenation of tetrahydropyrazine: a synthetic intermediate of the HIV protease inhibitor indinavar [S
] -Synthesis of piperazine 2-tertiary-butyl carboxamide, Tetrahedr
on Lett. , 1995, 36, 6419-6422. (C) Jennes
kens, L .; W. Mahy, J .; Den Berg, E .; M. M. de B. -V. Van der Hoef, I .; Luttenburg, J .; R
ecl. Trav. Chim. Pays-Bas 1995, 114, 97. 32. Wang, T .; Zhang, Z .; Meanwell, N .; A. Benzoylation of dianions: Preparation of monobenzoylated target secondary diamines, J. Mol. O
rg. Chem. , 1999, 64, 7661-7662. 33. (A) Adamczyk, M .; Fino, J .; R. Synthesis of procainamide metabolites, N-acetyldecetylprocainamide and decylprocainamide. Org. Prep. Proced. Int. 1996, 28, 470-4
74. (B) Wang, T .; Zhang, Z .; Meanwell, N .; A.
Site-Selective Monobenzoylation of Asymmetric Piperazine, J. Am. Org. Chem. 34. Masuwa, K .; Kitagawa, M .; Uchida, H .;
Bull Chem. Soc. Jpn. 1967, 40, 244-245. 35. M. Cooper, M .; E. Donald, D .; K. Tetrahe
dron Lett. 1993, 34, 1351-1354. 36. Bartoli et al., A) Tetrahedron Lett. 1989,
30, 2129. b) J. Chem. Soc. Perkin Trans. 11
991,2757. c) J. Chem. Soc. Perkin Trans. I
I 1991,657. 37. Chen, B.A. K. , Saksela, K .; , Andino, R and D.D.
Baltimore. 1994. Human immunodeficiency type 1 manifested by superinfection of a non-productively infected cell line with recombinant luciferase-encoding virus
Aspects of provirus latency. J. Virol, 68: 654-660.

[0012]

[Means for Solving the Problems]

Surprisingly, the compound of formula I or a pharmaceutically acceptable salt thereof is an effective antiviral agent, especially other antiviral agents, antiinfective agents, when used alone in the treatment of HIV.
It has also been found to be effective when used in combination with immunomodulators or HIV entry inhibitors.

[0013]   The present invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof:

[0014]

[Chemical 9]

Here, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ anikenyl, C ₃ -C ₆ cycloalkenyl, C ₂ -C ₆ alkynyl, halogen, CN, nitro, COOR ₆ or XR _7, wherein the alkyl and each cycloalkyl 1-3 identical or different optionally substituted by halogen, amino, OH , CN or NO ₂ ; R ₆ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or benzyl, each of said alkyl, cycloalkyl and benzyl being optionally 1 -3 may be substituted with the same or different halogen, amino, OH, CN or NO ₂ ; X is O, S or NR ₆ R ₇ ; R ₇ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkenyl, C ₂ -C ₆ alkynyl or C (O) R ₈
And each of said alkyl and cycloalkyl may be optionally substituted with 1-3 same or different halogen, OH, amino, CN or NO ₂ ; R ₈ is H, C ₁ -C ₆ alkyl Or C ₃ -C ₆ cycloalkyl;

[0016]

[Chemical 10]

[0017] Is;   R₉ , R_Ten, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ , R_{twenty one}And R_{twenty two}Are independently H and C₁ -C₆ Alkyl, C₃ -C₆ Cycloa
Rukiru, C₂ -C₆ Anikenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Al
Quinyl, CR_{twenty three}R_{twenty four}OR_{twenty five}, COR₂₆, COOR₂₇Or C (O) NR₂₈R₂₉And
Each of said alkyl and cycloalkyl is optionally 1-3 identical or different
Halogen, amino, OH, CN or NO₂ May be replaced with;   R_{twenty three}, R_{twenty four}, R_{twenty five}, R₂₆, R₂₇, R₂₈And R₂₉Are independently H and C₁ -C ₆  Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Shi
Chalkenyl or C₂ -C₆ Alkynyl;   Ar is a 4-7 membered aromatic ring, wherein the aromatic ring is O, S, N and NR.₆ Consists of
It may have 1-5 heteroatoms independently selected from the group, and if desired
B group may form a condensed ring;   B is phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, full
A group selected from the group consisting of oleenyl and anthracenyl; or 2-furyl, 3-
Furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyryl
Dil, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, iso
Oxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-
Triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pi
Razinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolidi
Nil, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo
[B] Furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimi
Dazolyl, benzthiazolyl, purinyl, 4H-quinolidinyl, quinolinyl, a
Soquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phena
Hetero selected from the group consisting of dinyl, phenothiazinyl and phenoxazinyl.
An aryl group;   B and the 4-7 membered aromatic ring are each independently R₃₀, R₃₁, R₃₂, R₃₃And R ₃₄ 1 to 5 substituents independently selected from   Ra and Rb are independently H and C_1-6 Alkyl or phenyl;   Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pi
Radil, quinolyl, 3,5-dimethylisoxazolyl, isoxazolyl, 2
-Methylthiazolyl, thiazolyl, 2-thienyl, 3-thienyl or pyrimidyl
Is;   p is 0-2;   R₃₀, R₃₁, R₃₂, R₃₃And R₃₄Are independently H and C₁ -C₆ Alkyl,
C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkeni
Le, C₂ -C₆ Alkynyl, halogen, CN, nitro, C (O) R₃₅, COXR ₃₆ , Hydroxy, COOR₆ , Hydroxymethyl, trifluoromethyl, trif
Luoromethoxy, C-[(C₁ -C_Four ) -Straight or branched alkyl], O-ben
Zil, O-phenyl, 1,2-methylenedioxy, OC (O) C_1-6 Alkyl,
SC (O) C₁ -C₆ Alkyl, S (O) mC₁ -C₆ Alkyl, S (O)₂ N
RaRb, amino, carboxy, OZ, CH₂ -(CH₂ ) P-Z, O- (C
H₂ ) P-Z, (CH₂ ) P-O-Z, CH = CH-Z or XR₃₇And the
Rukyl and cycloalkyl are optionally 1-3 same or different halogen,
Mino, OH, CN or NO₂ May be replaced with;   m is 0-2;   R₃₅And R₃₆Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Is alkyl;   R₃₇Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Al
Kenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Alkynyl, C (O) R₃₈or
Is C (O) OR₃₉And each of said alkyl and cycloalkyl is optionally 1
-3 identical or different halogen, amino, OH, CH or NO₂ Replaced by
May be:   R₃₈And R₃₉Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Alkyl, wherein the alkyl and cycloalkyl are optionally 1-3 identical or
Are different halogens, amino, OH, CN or NO₂ May be replaced with
R₃₉Is not H;   R₄₀Is (CH₂ ) N-Y, where n is 0-6;   Y is selected from the following (1) and (2); (1) H, C₁ -C₆ Alkyl, C ₃  -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkenyl
, C₂ -C₆ Alkynyl, halogen, CN, nitro, Ar, COOR₆ , COO
Ar, CONRaRb, TR₆ , NRaRb, -NC (O) NRaRb, -OC
(O) R₆ , -C [N (Ra)₂ ] = N-T-Rb, XR₆ , -C (O) R₆ ，
-C (O) Ar, -S (O) Ra or -S (O)₂ Ra, provided that Y is -S (
O) Ra or -S (O)₂ Ra is not H when Ra; and (2) O, S
, SO, SO₂ , N and NR₄₁A 1-3 membered heterocyclic group selected from the group consisting of:
The heterocyclic group is optionally R₆ R may be substituted with₄₁Is hydrogen (C₁ -C_Four )
-Straight or branched alkyl, (C₂ -C_Four ) -Straight or branched alkenyl or a
Selected from the group consisting of lukinyl;   T is S or O;   However, R₁ -R_Five , R₉ -R₁₆And R₃₀-R₃₄But at the same time not all hydrogen
And Ar is phenyl;   Also R₁ -R_Five , R₉ -R₁₆And R₃₀-R₃₄But at the same time not all hydrogen
And Ar is 2-furyl.

A further aspect of the invention is a pharmaceutical formulation containing an antivirally effective amount of a compound of formula I.

A further aspect of the invention is (a) an AIDS antiviral agent, (b) an anti-inflammatory agent, (C) an immunomodulator and (d).
A pharmaceutical preparation effective for the treatment of HIV infection, which further comprises an antiviral effective amount of a therapeutic agent for AIDS selected from the group consisting of HIV entry inhibitors.

A further aspect of the invention is a virus characterized in that an antivirally effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof is administered to a mammal (eg H.
IV) is a method of treating mammals, including humans infected with:

[0021]

[Chemical 11]

Here, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ anikenyl, C ₃ -C ₆ cycloalkenyl, C ₂ -C ₆ alkynyl, halogen, CN, nitro, COOR ₆ or XR _7, wherein the alkyl and each cycloalkyl 1-3 identical or different optionally substituted by halogen, amino, OH , CN or NO ₂ ; R ₆ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or benzyl, each of said alkyl, cycloalkyl and benzyl being optionally 1 -3 may be substituted with the same or different halogen, amino, OH, CN or NO ₂ ; X is O, S or NR ₆ R ₇ ; R ₇ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkenyl, C ₂ -C ₆ alkynyl or C (O) R ₈
And each of said alkyl and cycloalkyl may be optionally substituted with 1-3 same or different halogen, OH, amino, CN or NO ₂ ; R ₈ is H, C ₁ -C ₆ alkyl Or C ₃ -C ₆ cycloalkyl;

[0023]

[Chemical 12]

[0024] Is;   R₉ , R_Ten, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ , R_{twenty one}And R_{twenty two}Are independently H and C₁ -C₆ Alkyl, C₃ -C₆ Cycloa
Rukiru, C₂ -C₆ Anikenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Al
Quinyl, CR_{twenty three}R_{twenty four}OR_{twenty five}, COR₂₆, COOR₂₇Or C (O) NR₂₈R₂₉And
Each of said alkyl and cycloalkyl is optionally 1-3 identical or different
Halogen, amino, OH, CN or NO₂ May be replaced with;   R_{twenty three}, R_{twenty four}, R_{twenty five}, R₂₆, R₂₇, R₂₈And R₂₉Are independently H and C₁ -C ₆  Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Shi
Chalkenyl or C₂ -C₆ Alkynyl;   Ar is a 4-7 membered aromatic ring, wherein the aromatic ring is O, S, N and NR.₆ Consists of
It may have 1-5 heteroatoms independently selected from the group, and if desired
B group may form a condensed ring;   B is phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, full
A group selected from the group consisting of oleenyl and anthracenyl; or 2-furyl, 3-
Furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyryl
Dil, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, iso
Oxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-
Triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pi
Razinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolidi
Nil, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo
[B] Furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimi
Dazolyl, benzthiazolyl, purinyl, 4H-quinolidinyl, quinolinyl, a
Soquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phena
Hetero selected from the group consisting of dinyl, phenothiazinyl and phenoxazinyl.
An aryl group;   B and the 4-7 membered aromatic ring are each independently R₃₀, R₃₁, R₃₂, R₃₃And R ₃₄ 1 to 5 substituents independently selected from   Ra and Rb are independently H and C_1-6 Alkyl or phenyl;   Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pi
Radil, quinolyl, 3,5-dimethylisoxazolyl, isoxazolyl, 2
-Methylthiazolyl, thiazolyl, 2-thienyl, 3-thienyl or pyrimidyl
Is;   p is 0-2;   R₃₀, R₃₁, R₃₂, R₃₃And R₃₄Are independently H and C₁ -C₆ Alkyl,
C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkeni
Le, C₂ -C₆ Alkynyl, halogen, CN, nitro, C (O) R₃₅, COXR ₃₆ , Hydroxy, COOR₆ , Hydroxymethyl, trifluoromethyl, trif
Luoromethoxy, C-[(C₁ -C_Four ) -Straight or branched alkyl], O-ben
Zil, O-phenyl, 1,2-methylenedioxy, OC (O) C_1-6 Alkyl,
SC (O) C₁ -C₆ Alkyl, S (O) mC₁ -C₆ Alkyl, S (O)₂ N
RaRb, amino, carboxy, OZ, CH₂ -(CH₂ ) P-Z, O- (C
H₂ ) P-Z, (CH₂ ) P-O-Z, CH = CH-Z or XR₃₇And the
Rukyl and cycloalkyl are optionally 1-3 same or different halogen,
Mino, OH, CN or NO₂ May be replaced with;   m is 0-2;   R₃₅And R₃₆Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Is alkyl;   R₃₇Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Al
Kenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Alkynyl, C (O) R₃₈or
Is C (O) OR₃₉And each of said alkyl and cycloalkyl is optionally 1
-3 identical or different halogen, amino, OH, CH or NO₂ Replaced by
May be:   R₃₈And R₃₉Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Alkyl, wherein the alkyl and cycloalkyl are optionally 1-3 identical or
Are different halogens, amino, OH, CN or NO₂ May be replaced with
R₃₉Is not H;   R₄₀Is (CH₂ ) N-Y, where n is 0-6;   Y is selected from the following (1) and (2); (1) H, C₁ -C₆ Alkyl, C ₃  -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkenyl
, C₂ -C₆ Alkynyl, halogen, CN, nitro, Ar, COOR₆ , COO
Ar, CONRaRb, TR₆ , NRaRb, -NC (O) NRaRb, -OC
(O) R₆ , -C [N (Ra)₂ ] = N-T-Rb, XR₆ , -C (O) R₆ ，
-C (O) Ar, -S (O) Ra or -S (O)₂ Ra, provided that Y is -S (
O) Ra or -S (O)₂ Ra is not H when Ra; and (2) O, S
, SO, SO₂ , N and NR₄₁A 1-3 membered heterocyclic group selected from the group consisting of:
The heterocyclic group is optionally R₆ R may be substituted with₄₁Is hydrogen, (C₁ -C_Four
) -Straight or branched alkyl, (C₂ -C_Four ) -Straight or branched alkenyl or
Selected from the group consisting of alkynyl;   T is S or O;

In a preferred embodiment, the compounds of formula I and formula II are compounds wherein Ar is phenyl, furyl,
Included are compounds that are isoxazolyl, thiophenyl, pipetizolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, piperazinyl, thiazolyl, imidazolyl or thiadiazolyl. Also

[0026]

[Chemical 13] And

[0027]   R₉ , R_Ten, R₁₁, R₁₂, R₁₃, R₁₄And R₁₅Are each H, and R ₁₆ Compounds of formula I and II in which is methyl are also preferred.

Also preferred are compounds of formula I and II wherein R ₂ is H, fluorine or methoxy.

Also preferred are compounds of formula I and II wherein R ₁ , R ₃ and R ₄ are each H.

[0030]

DETAILED DESCRIPTION OF THE INVENTION

Process for the synthesis of novel indoleoxoacetylpiperazine alonags of formula I and anti-HI
V-1 activity is summarized below.

Chemistry: The present invention relates to compounds of formula I, their pharmaceutical preparations and their use in patients infected with or possibly infected with HIV. The terms in the compounds of formula I, including their pharmaceutically acceptable salts, have the following meanings:

[0032]

[Chemical 14]

The term “C _1-6 (or C ₁ -C ₆ ) alkyl” (unless otherwise stated) is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl. Etc. means a straight chain or branched chain alkyl group. Similarly, "C _2-6 (or C ₂ -C ₆₎ alkylene and" C _2-6 (or C ₂ -C ₆₎ alkynyl "
Includes straight or branched chain groups.

The term “pharmaceutically acceptable salt” is used to include non-toxic base addition salts.
Non-limiting examples of preferred salts include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, metasulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, amanitic acid, salicylic acid, Those derived from organic and inorganic salts such as phthalic acid are included.

[0035]   "Halogen" means chlorine, bromine, iodine or fluorine.

In the method of the present invention, the term “antivirally effective amount” is an amount sufficient to show a meaningful patient benefit, especially for the cure of disease states characterized by inhibition of antiviral infection, including HIV infection. By effective total amount of each active ingredient of this method is meant. When applied to an individual active ingredient alone, the term refers to that ingredient alone. When used in combination, the term, whether used in combination, sequentially or simultaneously, refers to the total amount of active ingredients which produces the desired antiviral effect. "
The term "treatment, treatment, treatment" means preventing or ameliorating diseases caused by viral infection, including HIV infection.

The present invention also relates to the combination of a compound of the invention together with one or more agents effective in the treatment of AIDS. For example, a compound of the present invention may be combined with an effective amount of an AIDS antiviral agent, immunomodulatory agent, anti-infective agent or vaccine, as shown in the following table, regardless of either pre-exposure and / or post-exposure period: It can be effectively administered. Antiviral agent:

Drug name Manufacturer's indication 097 Hoechst / Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) Ampreniver GlaxoWelcome HIV infection, AIDS, 141W94 ARC (protease inhibitor GW141 inhibitor) Avacover (1592U GlaxoWelcome HIV infection, AIDS, 89) GW1592 ARC (RT inhibitor) Asemannan Carrington Labs ARC (TX, Irvine) Acyclobarvalose welcome HIV infection, AIDS, ARC, (in combination with AZT) AD-439 Tanox Bio System HIV infection, AIDS, Muzu ARC AD-519 Tanox Biosystem HIV infection, AIDS, Muzu ARC Ensis HIV-infected sill AL-721 Etigen (CA, Losan ARC, PGL Zels) HIV-positive, AIDS alpha interfero Glaxo-welcome Kapoli sarcoma, HIV-n (combined with Retrovir) Ansamycin Adri Laboratories ARC LM427 (OH, Dublin) Elvamont ( CT, Stanford) PH neutralizing antibody Advanced Bioterra AIDS, ARC Abnormality of instability Interppy Concepzelon (MD, Rockville) AR177 Aronex Farm HIV infection, AIDS, ARC beta Fluoro-ddA National Cancer Society AIDS-related disease BMS-232623 Bristol Myers HIV infection, AIDS, (CGP-73547) Quive / Novatis ARC (Protease inhibitor ) BMS-234475 Same as above HIV infection, AIDS, (CGP-61755) ARC (Protease inhibitor) CI-1012 Warner Lambert HIV-1 infection Cidfovar girder science CMV retinitis, herpes, papilloma Wils curdlan sulfate AJI Pharma USA HIV Infected Cytomegalovirus Med Immun CMV Retinitis Immun Globulin Cytoben Syntex Visual Fear CMV Cancyclobar Peripheral CMV Retinitis Delaviridin Pharmacia Upji HIV Infection, AIDS, Young ARC (RT Inhibitor) Textran Sulfef Ueno Pharmaceuticals (Osaka) AIDS, ARC, HI-to-V positive Asymptomatic ddC Hoffman-Larosche HIV infection, AIDS, dideoxycytidine ARC ddI Bristol-Meier HIV infection, AIDS, dideoxyinosine squib ARC; combined with AZT / d4T DMP-450 AVID HIV infection, AIDS, (NJ, Camden) ARC (protease inhibitor) Efavirenz DuPont Merck HIV infection, AIDS, (DMP266) ARC Nucleoside (−) 6-chloro-4-RT inhibitor) (S) -Cyclopropylethynyl-4 (S) -trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, Stoculin EL10 Elancorp, PLC HIV infection (GA, Gainesville) Huam Cyclober Smith Klein Herpes zone, Herpes simplex FTC Emory University HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS840 Reed HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 Hoechst Marion Rose, HIV infection, AIDS, le ARC (non-nucleoside reductase inhibitor) Hypericin VIMRx farm HIV infection, AIDS, ARC Recombinant human Triton Biosaie AIDS, Kapoli Sarcoma, Interferon Veneces ARC (CA, Almeda) Interferon Alf Interferon Saie ARC, AIDS A-n3 Indinavar Merck HIV infection, AIDS, ARC, Asymptomatic HIV positive, AZT / ddI. The combination with / d dC is also ISIS2922 ISIS Pharmacy CMV Retinitis Ticalus KNI-272 National Cancer Society HIV-Kan Disease lamivudine, 3TC Glaxowelcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor), combination with AZT is also lobcover Bristol-Myers CMV infection Quibner finavar Agoron HIV infection, AIDS, Pharmaceutical ARCs (protease Inhibitor) Nevirapine Boehringer Ingle HIV infection, AIDS, Heim ARC (RT inhibitor) Novaprene Novaprene Labs HIV inhibitor (OH, Akron) Peptide T Peninsula Labus AIDS Octapeptide Sequen (CA, Belmont) Sphosphoro Astrafarm Prota CMV Retina Flame, HIV trisodium formate, other CMV infection PNU-140690 Fumarcia Upjo HIV infection, AID , ARC (Protease Inhibitor) Probucol Bayrex HIV Infection, AIDS RBC-CD4 Sheffield Medtech HIV Infection, AIDS, (TX, Houston) ARC Ritonaver Abbot HIV Infection, AIDS, ARC (Protease Inhibitor) Sakuinavar Hofane Laroche HIV Infection, AIDS, ARC (protease inhibitor) stavudine; d4T Bristol-Myers HIV infection, AIDS, didehydrodeoxythymic quib ARC Zimbala cyclobar Glaxowelcome genital HSV and CMV infected Virazole Ribavirin Viratech / ICN asymptomatic HIV positive, ( CA, Costa Mesa) LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Salcitabine Hoffman Laro Interview HIV infection, AIDS, ARC, AZT and combinations Jidobudin; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kapori sarcoma, other therapies and combination

Immunomodulator : Drug name Manufacturer's indication AS-101 Wyeth Ayast AIDS Bropirimine Pharmacia Upjo Progressive AIDS N-Asemannan Carrington Labs AIDS, ARC (TX, Irvine) CL246,738 American Cyanamid AIDS, Kaposi sarcoma Lederval Loves EL10 Elancorp, PLC HIV infection (GA, Gainsville) FP-21399 Fukiimunofarm HIV fusion block with CD4 + cells Gamma interferon Genetech ARC, w / TNF (tumor death factor) in combination with granulocytic macrogenetics Suins AIDS Phage colony stimulating factor Chichuto Sandoko Same as above Hoechst Roselim AIDS Nex Same as above Cielin Proe AIDS, AZT HIV core particle immunos roller seropositive HIV thymulant IL-2 cetus AIDS, w / AZT and interleukin-2 in combination, same as above Hoffmann, Larosheim AIDS, ARC, HI-nex V, w / AZT in combination, same as above Tiron AIDS, CD4 Cell number (Aldesulquin) increased immunoglobulin intercutter biological pediatric AIDS, Venus (human) (CA, Berkeley) IMREG-1 in combination with AZT IMREG-1 IMREG AIDS, Kaposi's sarcoma, (New Orleans) ARC, PGL IMREG-2 Ibid. Imthiol Diethyldimeliax Instiichi AIDS, ARC Thiocarbamate sute alpha-2 Schielepro Kaposi's sarcoma, AZT, A Interferon Methionine in combination with IDS -Enkepha TNI Pharmacyte AIDS, ARC Lycal (IL, Chicago) MTP-PE Ciba Geigy Kaposi's sarcoma Muramyl-tripeptide granules Amgen AIDS, AZT and combined colony stimulating factor Remuune immun response co-immunotherapy prCD4 recombinant soluble Higenentech AIDS, ARC and CD4 rCD4-IgG AIDS, ARC Hybrid Recombinant Soluble Human CD4 Viogen AIDS, ARC Interferon alfa Hoffman-Laroche Kaposi's Sarcoma 2a AIDS, ARC, ATZ Infectious Soluble T4 in combination with SK and F106528. Timopentin Immunobiology Lisa HIV infection-Chinese Institute (NJ, Annandale) Tumor death factor: TNF diene ARC, in combination with gamma interferon

Anti-infective: Drug name Manufacturer's indication Clindamycin and Pripharmacia Upjo PCP McKinn fluconador Pfizer Cryptococcal Meningititis, Candidiasis Pastel Squibcorp Oral Candidiasis Nistatin Pastil Ornidyl Mereldau PCP Efro Nitin pentamidine Isethene Lifomed PCP Treatment (IM and IV) (IL, Rosemont) Trimethoprim Antibacterial Trimethoprim / Sulf Antibacterial Apritrexime Valose Welcome PCP Treatment Inhalation Mentamidine Isefison Corporesis PCP Prevention Thionate Spiramycin Lone Puran Diale Cryptosporial Aintraconazole-R Janssen-Farm Histoplasmosis; 51211 Cryptococcal Menin Gite Strimetrexate Warner Lambert PCP Dunorubicin Nexter, Sequus Kaposi's sarcoma Recombinant human erythropoie Orthofarm Coop Intense anemia of recombinant human growth hormone Serono AIDS-related debilitation, Kahexymegestrol Asetet Bristol-Myers AIDS Associated anemia treatment Tosquibutestosterone Alza, SmithKline AIDS-related debilitating whole intestinal nutrition Nowick Eatonfough AIDS-related diarrhea, pharmacological and malabsorption

The compounds of the present invention may also be used in combination with other classes of agents for treating AIDS called HIV entry inhibitors. Examples of these HIV entry inhibitors are DR
UGS OF THE FUTURE 1999, 24 (12), pp. 135
5-1362; CELL, Vol. 9, pp. 243-246, 1999, 10
． 29; and DRUG DISCOVERY TODAY, Vol. 5, No.
5, 2000, 5, pp. 183-194.

The range of the combination of the compound of the present invention and the AIDS antiviral agent, immunomodulator, antiinfective, HIV entry inhibitor or vaccine is not limited to the above, but in principle A
It includes any combination with any pharmaceutical composition effective in the treatment of IDS.

A preferred combination is a compound of the invention with an inhibitor of HIV protease and / or H
Simultaneous or alternating treatment with a non-nucleoside inhibitor of IV reverse transcriptase. The optional fourth component in this combination is AZT, 3TC, ddC or d.
It is a nucleoside inhibitor of HIV reverse transcriptase such as dI. H
A preferred inhibitor of IV protease is indinavar or N- (2 (R) -hydroxy-1- (S) -indanyl) -2 (R) -phenylmethyl-4- (S)-.
Hydroxy-5- (1- (4- (3-pyridyl-methyl) -2 (S) -N '-(
t-Butylcarboxamide) -piperazinyl))-pentanamide ethanolate sulfate, which can be synthesized according to the method described in US Pat. No. 5,413,999. Other preferred protease inhibitors are nelfina
vir) and ritonavir. Another preferred inhibitor of HIV protease is sequinavir, which is 6
00 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
There is. For the production of ddC, ddI and AZT EPO 0,484,071
It is also described in. These combinations have a significant effect on limiting the spread and extent of HIV infection. Examples of preferred combinations include the following (1) indinavar and efavirenz and optionally AZT and / or 3TC and / or ddI and / or ddC; (2) indinavar and AZT and / or ddI and / or ddC and / or Any of 3TC, especially indinavar, AZT and 3TC; (3) stavudine and 3TC and / or zidovud
dine); (4) Zidovudine and lamivudine and 141W94 and 1592U89; (5) Zidovudine and lamivudine in combination.

In these combinations, the compound of the invention and the other active agent may be administered separately or together. Also, the administration of one drug may be before, after, or after the administration of the other drug.

Methods for making compounds of Formula I are shown in Schemes 1-13 and are further illustrated in Tables 5-8.

[0046]

[Chemical 15]

The starting material, Indole 1 (Scheme 1), was prepared as described in Gribble, G .; (Ref. 2
4) or Bartoli et al. (Ref. 36). Indole 1 is a method described in the literature (Lingens F
． Et al., Ref. 25) THF (tetrahydrofuran) of oxalyl chloride according to
Alternatively, treatment with an ether solution yields the desired glyoxyl chloride 2. The intermediate glyoxyl chloride 2 is then coupled under basic conditions with benzoylpiperazine 3 to yield (Desai, M. et al., Ref. 26) 4.

[0048]

[Chemical 16]

Treatment of indole-3-gryloxyl chloride 2 (Scheme 2) with t-butyl 1-piperazinecarboxylate 5 yields the combined product 6. Deprotection of the 6 protecting group is carried out with 20% (trifluoroacetic acid) TFA / CH ₂ Cl ₂ to give 7.
This product is coupled with a carboxylic acid in the presence of polymer supported 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) to give product 8.

[0050]

[Chemical 17]

For Examples 58-81, piperazine 7 (Scheme 3) was added to Boc- in the presence of EDC.
Treatment with protected aminobenzoic acid yields 8a. Part of product divided into Boc
Subject to TFA to remove the group to give the amino derivative 9.

[0052]

[Chemical 18]

For Examples 82-89, piperazine (Scheme 4) is treated with acetoxybenzoic acid in the presence of EDC to give 8b. A portion of the product was divided and subjected to LiOH hydrolysis to remove the acetate group to give the hydroxy derivative 10.

Compounds containing a substituted piperazine are made using the general method shown in Schemes 5-13.

Substituted piperazines are commercially available from Aldrich and are described in the literature (
Behun et al., Ref. 31 (a), scheme 5, eq. 01). Hydrogenation of the alkyl-substituted piperazine under pressure of 40-50 psi in ethanol gives the substituted piperazine. When the substituent is an ether or an amide, the piperazine system can be partially reduced to tetrahydropiperazine (Rossen et al.,
Ref. 31 (b), Scheme 5, eq. 02). Carbonyl-substituted piperazine is obtained under the same conditions as above using commercially available dibenzylpiperazine (Scheme 5,
eq. 03).

[0056]

[Chemical 19]

2-trifluoromethylpiperazine (Jenneskens et al., Ref. 31)
c) was made by a 4-step route (Scheme 6). With Lewis acid TiCl ₄
N, N'-dibenzylethylenediamine 11 is reacted with trifluoropyruvate 12 to form hemiacetal 13, which is then Et ₃ Si in CF ₃ COOH.
Reduction with H at room temperature gives lactam 14. Next, the lactam 14 is reduced by LiAlH ₄ treatment to give 1,4-dibencil-2-trifluoromethylpiperazine 15. Finally, compound 15 was hydrogenated in HOAc to give the desired product, 2
-Trifluoromethylpiperazine 16 is obtained.

[0058]

[Chemical 20]

Monobenzoylation of symmetrically substituted piperazines can be carried out using one of the following methods (Scheme 7). (A) The acetic acid solution of piperazine was treated with acetyl chloride to obtain the desired monobenzoylated piperazine (Desai et al., Ref. 26, Scheme 7, eq. 04). (B) Symmetric piperazine was treated with 2 equivalents of n-butyllithium and then benzoyl chloride was added at room temperature (Wang et al., Ref. 32).
, Scheme 7, eq. 05).

[0060]

[Chemical 21]

Monobenzoylation of an asymmetrically substituted piperazine can be performed using one of the following methods (Scheme 8). All methods here are illustrated with monoalkyl-substituted piperazines. (A) Treatment of asymmetric piperazine with 2 equivalents of n-butyllithium, followed by addition of benzyl chloride at room temperature to give a mixture of the two regio isomers, which were chromatographed (Wang et al., Ref. 32 and 33 (b), Scheme 8
, Eq. 06); (b) conversion of benzoic acid to its pentafluorophenyl ester, followed by further reaction with 2-alkylpiperazine to give monobenzoylpiperazine with a benzoyl group attached to the nitrogen with less steric hindrance (Adamczyk et al., R
ef. 33 (a), scheme 8, eq. 07); (c) a mixture of piperazine and methyl benzoate 2-diamine aluminum chloride in methylene chloride.
Treatment for 4 days gave monobenzoylpiperazine with a benzoyl group attached to the less sterically hindered nitrogen (Stem 8, eq.08); (d) Asymmetric piperazine was treated with 2 equivalents of n-butyllithium, then triethylsilyl. A THF solution of chloride and benzoyl chloride was added at room temperature to obtain a monobenzoylpiperazine having a benzoyl group attached to a nitrogen having a large amount of steric hindrance (Wang et al., Ref. 33 (b), Scheme 8, eq.09). Monobenzoylation with benzoyl chloride when the 2-position substituent is an ester or amide occurs at the less sterically hindered nitrogen of piperazine using triethylamine as the base in THF (Scheme 8, eq.10).

[0062]

[Chemical formula 22]

In the case of tetrahydropyrazine (Scheme 9, eq.11), the monobenzoylation was carried out under the same conditions as in Scheme 10, Formula 10, as in the conventional example (Rossen et al., Ref. 31 (b)). It occurs in people with many disabilities.

[0064]

[Chemical formula 23]

In addition, the ester group can be selectively reduced with NaBH ₄ in the presence of benzamide (Masuzawa et al., Ref. 34), which is shown in Scheme 10.

[0066]

[Chemical formula 24]

[0067]   Hydrolysis of ester group to acid:

The ester group on either the piperazine linkage or the indole nucleus can be converted to K ₂ CO ₃ (Scheme 11, eq. 13) or NaOM as a base in methanol and water.
It can be hydrolyzed to the corresponding acid under basic conditions using e (Scheme 11, eq.14) and the like.

[0069]

[Chemical 25]

Coupling reaction:

[0071]

[Chemical formula 26]

The target product 18 was obtained by reacting the substituted benzoylpiperazine or tetrahydropyrazine (17) in CH ₂ Cl ₂ with glyoxyl chloride 2 using i-Pr ₂ NEt as the base.

In the case of coupling reactions using 3-hydroxymethylbenzoylpiperazine, the hydroxyl group was temporarily protected as its TMS (trimethylsilyl) ether with BSTFA (N, O-bistrimethylsilyl) fluoroacetamide (Furber et al. , Ref. 35). The unprotected nitrogen atom was then reacted with glyoxyl chloride 2 to form the desired diamine. The TMS protecting group was removed during operation to give free hydroxymethylpiperazinediamine 19 (Scheme 13).

[0074]

[Chemical 27]

Antiviral activity: The antiviral activity of the compounds of Examples 1-34 was tested for HIV in the presence of 10 μM compound.
-1 was measured in MT-2 cells acutely infected with BRU strain (CD4-positive T-lymphoid cell line). Viral load was quantified 6 days post infection using a reverse transcriptase assay (Potts, Ref. 27). The antiviral results are shown in Table 1. Cytotoxicity was measured by incubating cells in the presence of serially diluted compounds and cell viability was measured using XTT dye reducing assay (Weislow).
, Ref. 28). The 50% cytotoxic concentration of all compounds is significantly higher than 10 μM, indicating that these compounds are relatively non-toxic.

The antiviral activity of the compounds of Examples 35-215 was measured in HeLaCD4CCR5 cells infected with a single round infectious HIV-1 reporter virus in the presence of the compound at a concentration of 10 μM or less. Viral infection was quantified 3 days after infection by measuring luciferase display from integrated viral DNA in infected cells. The% inhibition of each compound was determined by quantifying the level of luciferase display in cells infected in the presence of each compound as% of that observed for cells infected in the absence of compound and subtracting the measurement from 100. It was The compounds that show antiviral activity at no more than 10 μM concentration without appreciable toxicity are shown in Tables 1-4 and 9-13.

[0077]

[Table 1]

[0078]

[Table 2]

[0079]

[Table 3]

[0080]

[Table 4]

[0081]

[Table 5]

[0082]

[Table 6]

[0083]

[Table 7]

[0084]

[Table 8]

[0085]

[Table 9]

[0086]

[Table 10]

[0087]

[Table 11]

[0088]

[Table 12]

[0089]

[Table 13]

[0090]

[Table 14]

[0091]

[Table 15]

Experimental Method: Biology: Abbreviations will be explained. “ΜM” means micromolar. “ΜCi” means microcurie. "Μl" means microliter. "Μg" means microgram. "M" means moles. "Μm" means micromolar. "MM" means millimole. "A" is% inhibition data and represents the mean of at least 2 experiments with at least duplicate measurements in each experiment. "RT" means reverse transcriptase. The materials and experimental methods used to obtain the antiviral activity results of Examples 1-34 are set forth below.

Cells-MT-2 grown in Roswell Park Memorial Institute
T-strain: (RPMI) 1640 medium (Life Technologies, MD, Gaithersburg) containing 10% lethal bovine serum (FBS, Sigma, MO, St. Louis) virus-laboratory HIV-1 strain BRU. Infectivity assay (Johnson, V
． A. And R.A. E. Byrton, 1990).

Experiment: 1. MT-2 cells (Harada et al., Ref. 30) at 1 × 10 ⁵ cells / ml
Were infected with HIV-1 BRU at a multiplicity of infection of 0.005 in RPMI 1640 medium containing 10% lethal bovine serum at a concentration of. 2. Compounds were added at a concentration of 20 μM in 96 well plates at 10 10 per well.
100 μl of RPMI 1640 medium containing% lethal bovine serum was added. 100 μl of 3.1 × 10 ⁵ / ml of infected MT-2 cells was added to each well in these plates to give a final cell concentration of 5 × 10 ⁴ cells / ml and a final compound concentration of 1
It was set to 0 μM. 4. Samples were incubated at 37 ° C and removed 6 days after infection. 5. HIV-1 replication was quantified by measuring HIV-1 reverse transcriptase (RT) present in cell-free supernatants (Rotts et al., Ref.
． 27). For each sample, 20 μl of cell-free supernatant was mixed with 40 μl of RT cocktail [42 μM tris (hydroxymethyl) aminomethane pH 7.8 (Sigma,
MO, St. Louis), 63 μM Potassium Chloride (Marincklot, KT, Paris), 2 μM Dithiothreitol (Sigma, MO, St. Louis), 4 μM Magnesium Chloride (Marinclerot, KT, Paris), 4 μg / l polyadenylic acid (Pharmacia, NJ, Piscataway), 1.3 μg / ml of oligonucleotide deoxymidine _12-18 (Pharmacia, NJ, Piscataway), 0.04
% (Octylphenoxy) -polyethoxyethanol (Nonidet P-40,
(Sigma, MO, St. Louis) and 17 μCi / ml 3H-deoxymidine 5
'-Triphosphate (NEN, MA, Boston) .Incubate for 1 hour at 37 ° C, then aliquot 1 μl of each reaction into diethylaminoethylcellulose (DE-
81) Place on filter paper (Whatman, OR, Hillsboro), dry, 0.3M
Sodium Chloride (Fisher Scientific, PA, Pittsburgh)
, 30 mM sodium citrate pH 7.0 (Sigma, MO, St. Louis) four times and twice in 95% ethanol. Bound radioactivity was quantified by scintillation counting. 6. The percent inhibition of each compound was quantified as the level of HIV-1 replication in the presence of each compound as a% of control without compound, and the measurement was subtracted from 100. 7. To determine the cytotoxicity of the compounds, uninfected cells were incubated with a series of concentrations of each compound for 3-6 days. Cell viability was measured by the XTT {2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -5-[(phenylamino) carbonyl] -2H-tetrazolium hydroxide} dye reduction method (Weislow et al., Re.
f. 28). The percentage of viable cells in the compounds containing the wells compared to untreated controls was determined. 50% cytotoxicity was calculated as the drug concentration that reduced the percentage of viable cells to 50% of them in untreated cells.

The materials and methods for measuring antiviral activity in Examples 35-215 are as follows: Cells: virus production-human embryonic kidney cell line, 293, 10% lethal bovine serum. Proliferated in Dulbecco's modified Eagle medium (Life Technologies, MD, Geisersberg) containing (FBS, Sigma, MO, St. Louis). Viral infection-displaying human epithelial cell line, HeLa, HIV-1 receptor CD4 and CCR5, 10% lethal bovine serum (FBS, Sigma, MO,
St. Louis) containing Dulbecco's modified Eagle medium (Life Technologies,
Proliferated in MD, Geysersburg) and supplemented with 0.2 mg / ml of dieneticin (Life Technologies, MD, Geisberg) and 0.4 mg / ml of Zeocin (Invitrogen, CA, Carlspad).

Virus-human embryonic kidney 293 cells were co-infected with an HIV-1 envelope DNA display vector and a proviral cDNA containing an envelope excision mutant and the luciferase reporter gene was added to the site of the HIV-1 nef sequence. (Chen, 1994), the infection procedure was performed using the Lipofectamine plus reagent described by the manufacturer (Life Technologies, MD, Geysersburg).

Experiment: 1. 100 containing 10% lethal bovine serum at a concentration of 1.20 μM or less
Compounds were added to HeLa CD4 CCR5 cells plated in 96 well plates at a cell density of 5 × 10 ⁴ cells per well in μl of Dulbecco's modified Eagle's medium. 2. Replication-defective reporter virus in Dulbecco's modified Eagle medium was added to the plated cells and compounds at a multiplicity of infection (MOI) of 0.01 to give a final volume of 200 μl / well and a final compound concentration of 10 μM or less. 3. Samples were removed 72 hours post infection. 4. Virus D in cells infected with Luciferase Reporter Gene Assay Kid (Roche Molecular Biochemicals, IN, Indianapolis)
Viral infection was monitored by measuring luciferase display from NA. Infected cell supernatants were removed and 50 μl of Dulbecco's modified Eagle's medium (without Phenol Red) and 50 μl of each luciferase assay reagent reconstituted as described by the manufacturer (Roche Molecular Biochemicals, IN, Indianapolis). Per well) was added. Then, luciferase activity was quantified by measuring luminescence using a Wallac microbeta scintillation counter. 5. The inhibition rate of each compound was calculated by quantifying the level of luciferase display in cells infected in the presence of each compound as a percentage of the result in cells infected in the absence of compound and subtracting the measured value from 100. .

References: Chen, B. K. , Saksela, K .; , Andino, R .; And D. B
altimore. 1994. Distinguishable aspects of human immunodeficiency type 1 provirus latency revealed by superinfection of cell lines infected non-productively with recombinant luciferase-encoding virus, J. Viol. 68: 654-6
60 (Ref. 37).

Chemistry: General: Unless otherwise specified, commercially available solvents and reagents were used as they were, and reactions were carried out under a nitrogen atmosphere. Silica gel 60 (particle size 0.040 to 0.063; E
Flash chromatography was performed on M Science Supply. ¹ HN
MR was recorded at 500 MHz unless otherwise noted and the chemical shift associated with the residual solvent signal is reported. The following standard acronyms were used to indicate multiple patterns: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), b (broad), app (apparent). All liquid chromatography (LC) was recorded on Shimadzu LC-10AS liquid chromatograph using SPD-10AV UV-bis detector and mass absorption measurement (
MS) was performed on a micromass platform for LC in electrospray mode.

LC / MS Method (ie Compound Identification) Unless otherwise stated, all compounds were analyzed using the following conditions: Column: YMC ODS S7 3.0 × 50 mm column Gradient: 100% Solvent A / 0% solvent B to 0% solvent A / 100% solvent B gradient time: 2 minutes retention time: 1 minute flow rate: 5 mL / min detector wavelength: 220 nm solvent A: 10% MeOH / 90% H ₂ O / 0.1 % Trifluoroacetic acid Solvent B: 10% H ₂ O / 90% MeOH / 0.1% trifluoroacetic acid The following conditions were used for HPLC analysis. Method A: Column YMC ODS-A C18 S7 3.0 × 50 mm Starting% B = 0 / Final% B = 100 Method B: Column YMC ODS-A C18 S7 3.0 × 50 mm Starting% B = 30 / Final% B = 100 C: Column PHX-LUNA C18 4.6 x 30 mm Starting% B = 0 / Final% B = 100

The preparative HPLC purified compound was diluted with methanol (1.2 mL) and purified on a Shimadzu LC-10A automated preparative HPLC system using the following method.

Preparative HPLC Method (ie Purification of Compounds) Purification Method: Initial gradient (40% B, 60% A) to final gradient (100% over 20 minutes.
% B, 0% A) and hold for 3 minutes (100% B, 0% A). Solvent A: 10% MeOH / 90% H ₂ O / 0.1% trifluoroacetic acid Solvent B: 10% H ₂ O / 90% MeOH / 0.1% trifluoroacetic acid Column: YMC C18 S5 20 × 100 mm column detector Wavelength: 220 nm Indole was commercially available or was prepared by a known method according to Bartoli's method (Ref. 36) or Gribble (Ref. 24).

[0103]   A representative indole synthesis is shown below.   Preparation of 4-fluoro-7-methylindole:

[0104]

[Chemical 28]

BC13 (44 mmol, 44 ml) was added to a flame dried 50 ml 3 neck flask.
, 1 M in benzene) and 100 mL of dry benzene at room temperature under N ₂ . The mixture was cooled to 0 ° C. and a solution of 5-fluoro-2-methylaniline (5 g, 40 mmol) in 10 ml of dry benzene was added dropwise over 10 minutes to give chloroacetonitrile (2.18 g, 48 mmol). Is added dropwise over 2 minutes, and Al is added once
Cl ₃ was added. After stirring for 5 minutes at 0 ° C., the ice bath was removed and the mixture was refluxed under N ₂ for 6 hours. The product mixture was cooled to room temperature and EtOAc / 1N HCl (300 m
L, ice and poured into 50:50 v: v). After separation, the aqueous layer was washed with EtOAc (2 x 1
(00 mL). Combine the combined organic layers with water (100 mL), brine (2 × 1).
(00 mL) and dried over MgSO ₄ . The solvent was removed under vacuum and the purified intermediate was used directly in the next step without further purification.

[0106]

[Chemical 29]

The above residue was dissolved in 100 mL EtOH. The mixture is then cooled to 0 ° C.,
A ₂ ml H ₂ O solution of NaBH ₄ was added dropwise. After stirring at 0 ° C. for 1 hour, the reaction mixture was diluted with H ₂
Quenched with O (10 mL). The solvent was removed under vacuum and the residue was washed with EtOAc (150
mL) and washed with brine (2 x 50 mL). The organic phase was dried over MgSO ₄ , the solvent was removed and the expected reducing intermediate was used directly in the next cyclization step.

[0108]

[Chemical 30]

The above intermediate of yellow oil was dissolved in 100 mL of EtOH and treated with K ₂ CO ₃ (11.0
g, 80 mmol) was added. The mixture was refluxed under N ₂ for 2 hours and cooled to room temperature. The solid was filtered through Celite and the solution concentrated in vacuo. The residue is EtOA
Dissolved in c (200 ml), washed with brine (2 x 50 mL) and dried over MgSO ₄ . The solvent was removed under vacuum to give a brown oil. This was purified by flash chromatography (12% EtOAc in hexane) to give 2.3 g of pure product (total yield 39
%) Was obtained. M + H, 150.0: retention time 1.297 seconds.

[0110] Synthesis of 4-ethoxyindole:

[0111]

[Chemical 31]

In an oven-dried 2-neck flask, 5 ml DMF and NaH (66 mg, 6 in oil)
0%, 1.65 mmol) was added. The mixture was cooled to 0 ° C. and 4-hydroxyindole (200 mg, 1.5 mmol) in 5 mL DMF was added dropwise over 10 seconds. After stirring for 30 minutes under N _{2, a 2} ml DMF solution of bromoethane was added dropwise and the mixture was continuously stirred for 2 hours while warming to room temperature. Remove the solvent under vacuum,
The crude 4-ethoxyindole obtained from the aqueous phase was purified by preparative HPLC to give pure 4-ethoxyindole.
201 mg (83%) of ethoxyindole were obtained; HPLC retention time 1.190.
Minutes.

[0113] Synthesis of 4-fluoro-7-carbomethoxyindole:

[0114]

[Chemical 32]

4-Fluoro-7-bromoindole (600 mg, 2.8 mmol) and Cu
1 mixture of CN (1.004 g, 11.2 mmol) in DMF (4 mL).
Refluxed for 6 hours. After cooling to room temperature, the reaction mixture was treated with ammonia in MeOH (30
(ml, saturated) solution and the residue was filtered off. The filtrate was added to a mixture of water (20 mL) / ammonia (20 mL, saturated aqueous solution) and extracted with EtOAc / ether (1/1) until TLC analysis showed no product in the aqueous phase. The organic phases were combined, washed with brine (2 × 200 mL) and water (200 mL), dried (MgSO ₄ ) and evaporated in vacuo to give 4-fluoro-7-cyanoindole as a tan solid (
310 mg, 69%).

[0116]

[Chemical 33]

KOH (13.04 g, 0.232 mol) in 14% H ₂ O / EtOH (50 m
L) 4-Fluoro-7-cyanoindole (900 mg, 5.60 mmol) was added to the solution. The mixture was refluxed for 12 hours, gradually cooled to room temperature and concentrated under vacuum to about 30 mL. The residue was acidified to pH 2 with HCl (˜5.5N aqueous solution). The precipitate was filtered, washed with excess water and dried under high vacuum to give 4-fluoro-7-carboxindole as a white solid (100% conversion). This was used without further purification.

[0118]

[Chemical 34]

(Trimethylsilyl) diazomethane (8
． 8 mL, 17.6 mmol, 2M in hexane) was added. The product mixture was stirred at room temperature for 30 minutes, quenched with excess acetic acid and evaporated in vacuo. The crude oil was purified by flash chromatography using a gradient eluent (hexane to 10% EtOAc / hexane) to give methyl (4-fluoro) indole-7-carboxylate as a white solid (1.04 g, 2 steps). 83%). Preparation of 4-fluoroindole-7-carboxaldehyde:

[0120]

[Chemical 35]

4-Fluoro-7-bromoindole (1.0 g, 4.7 mmol) in THF
N-BuLi (5.6 mL, 2.5 M in hexane) at -78 ° C in (5 mL) solution.
Was added dropwise. The mixture was stirred at -78 ° C for 15 minutes, warmed to 5 ° C over 30 minutes and then recooled to -78 ° C. DMF (1.8 mL) was added, and the mixture was gradually warmed to room temperature. The reaction mixture was quenched with water and extracted with ether. The organic layer was dried over MgSO ₄ and concentrated to give 4-fluoro-indole-7-carboxaldehyde.

[0122]   Temporary manufacturing method of Examples 1-17 shown in Table 5:

[0123]

[Chemical 36]

To a solution of commercially available indole-3-glyoxylyl chloride I (3 g, 14.45 mmol) in CH ₂ CH ₂ at room temperature was added t-butyl 1-piperazinecarboxylate (
2.7 g, 14.45 mmol) and diisopropylethylamine (2.76 mL)
, 15.9 mmol) was added. This light brown solution was stirred for 2 hours at room temperature before LC /
The completion of the reaction was confirmed by MS analysis. The solvent was removed under vacuum and the residue was washed with ethyl acetate (25
0 mL) and diethyl ether (250 mL). Add this organic solution to water (
100 mL × 3) and washed with brine (50 mL), dried over MgSO _4, filtered, and concentrated. 20% trifluoroacetic acid (H ₂ Cl ₂ solution 3
0 mL was added. The solution was concentrated and the light brown solid was dried under vacuum to give the product II
Was obtained (3.5 g, 95%). LC / MS analysis confirmed the product to be 100% pure. This was used in the next step without further purification.

[0125]

[Chemical 37]

1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) (0.21 mmol) resin-bonded to piperazine indole-3-glyoxylamine II (0.03 mmol) and carboxylic acid ( RCOOH) (0.06
A solution of mmol) of dichloroethane (DCE) (1 mL) and DMF (dimethylformamide) (1 ml) was added. DCE was used when the carboxylic acid was inactive. The reaction mixture was stirred at room temperature for 12 hours. Product III was filtered and concentrated. 70
The product with a purity of less than% was diluted with methanol and purified using a Shimadzu automated preparative HPLC system.

[0127]   General method for making Examples 18-56 shown in Table 5:

[0128]

[Chemical 38]

A solution of the substituted indole IV (1 equivalent) in dry Et ₂ O was added to oxalyl chloride (1
． 2 eq.) Was added dropwise at 0 ° C. and the reaction mixture was warmed to room temperature or heated to 35 ° C. overnight if necessary. The intermediate substituted indole-3-glyoxylyl chloride V formed as a solid was filtered and washed with dry ethanol (2 x 1 mL) to remove excess oxalyl chloride. The product was then dried under vacuum to give the desired glyoxyl chloride V.

If the reaction of Et ₂ O was insufficient, the following method was used: Substituted indole I
Oxalyl chloride (1.2 eq) was added dropwise at 0 ° C. to a solution of V (1 eq) in dry THF (tetrahydrofuran). After 5 minutes the reaction mixture was warmed to room temperature or heated to ~ 70 ° C under nitrogen if necessary. After concentration in vacuo, the purified intermediate V was subjected to the next step without further treatment.

[0131]

[Chemical Formula 39]

Indole glyoxyl chloride V (benzoyl piperazine (1 eq) was added to a solution of dry THF in 1 eq at room temperature. The mixture was then cooled to 0 ° C. and diisopropylamine (1.3 eq) was added dropwise. After 5 minutes, the reaction mixture was warmed to room temperature and shaken for 3 hours, the resulting crude product IV was purified by preparative HPLC.
The results are shown in.

[0133]   General method for making Examples 58-63 shown in Table 5:

[0134]

[Chemical 40]

A solution of glyoxyl chloride V (1 equivalent) in CH ₂ Cl ₂ was added to t-butyl 1 at room temperature.
-Piperazinecarboxylate (1 eq) and diisopropylethylamine (1.
2 eq) was added. The solution was stirred at room temperature for 2 hours and then LC / MS analysis confirmed the completion of the reaction. The solvent was removed under vacuum and the residue was diluted with ethyl acetate and diethyl ether. The organic solution was washed with water (100 mL × 3) and brine (50 mL), dried over MgSO _4, filtered, and concentrated. To this solid was added 30 mL of 20% trifluoroacetic acid in CH ₂ Cl ₂ solution. The solution was concentrated and the light brown solid was dried under vacuum to give glyoxamide VII.

[0136]

[Chemical 41]

Piperazine glycol VII (0.1 mmol, 1 eq) in DMF (1 mL)
EDC (1.5 eq) and Boc-aminobenzoic acid (1.5 eq) at room temperature in solution
Was added. The reaction mixture was stirred at room temperature for 16 hours. Preparative HPL of crude product
Purification on C gave product VIII. General method for making Examples 65-73 shown in Table 5:

[0138]

[Chemical 42]

[0139]   50% TFA / CH in Boc protected derivative VIII (0.03 mmol)₂ Cl ₂  Was added. The reaction mixture was stirred at room temperature for 16 hours. Concentrate the product in vacuo
The product IX was obtained as the TFA salt. The purity of IX is high enough to require further purification.
I didn't.

[0140]   General method for making Examples 82-86 shown in Table 5:

[0141]

[Chemical 43]

Piperazine glyoxamide VII (0.1 mmol, 1 eq) in DMF (1 m
L) solution at room temperature with EDC (1.5 eq) and acetoxybenzoic acid (1.5 eq)
Was added. The crude product was purified by preparative HPLC to give product X.

[0143]   General method for making Examples 87-89 shown in Table 5:

[0144]

[Chemical 44]

To the acetate-protected derivative X (0.03 mmol, 1 eq) was added an aqueous solution of LiOH (3 eq) in THF / MeOH (1.5 mL, 1: 1). The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC to give the product X
Got I.

[0146]   General method for making Examples 64 and 74-81 shown in Table 5:

[0147]

[Chemical formula 45]

To a solution of Boc-protected aminobenzoic acid (5 mmol) in DMF (10 mL) was added pentafluorophenol (5 mmol) at room temperature, followed by EDC (5 mmol). The reaction mixture was stirred at room temperature for 3 hours. The crude product was diluted with CH ₂ Cl ₂ and washed with water, 0.1M HCl and brine. The organic layer was dried over MgSO _4, filtered, and concentrated. The pentafluorophenyl ester XII was used in the next reaction without further purification.

[0149]

[Chemical formula 46]

[0150]   (R) -2-Methylpiperazine was added to a stirred solution of DMF (15 mL) at room temperature under stirring.
A solution of fluorophenyl ester XII in DMF (2 mL) was added dropwise. Reaction mixture
The mixture was stirred at room temperature for 16 hours. CH crude product₂ Cl₂ Diluted with Na₂ CO ₃  (Saturated) and brine. The organic layer is MgSO_Four Dry with, filter and concentrate
did. Flash chromatography of the crude product (50% EtOAc / hexa
-10% MeOH / EtOAc) to give product XIII.

[0151]

[Chemical 47]

To a solution of indole-3-glyoxyl chloride V (1 eq) in CH ₂ Cl ₂ was added acylpiperazine XII followed by i-Pr ₂ NEt (3 eq). The reaction mixture was stirred at room temperature for 5 hours. It was then diluted with methanol and the product XIV was purified by preparative HPLC.

[0153]

[Chemical 48]

[0154]   50% TFA / CH to Boc protected derivative XIV (~ 0.03 mmol)₂ Cl ₂  (1.5 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. Product true
The product XV was obtained by concentrating in the air to obtain the product XV. The purity of XV was sufficient and did not require further purification.
.

[0155]   General method for making Examples 57 and 90 shown in Table 5:

[0156]

[Chemical 49]

To a solution of the substituted indole IV (1 eq) in CH ₂ Cl ₂ was added dropwise ethyl chlorooxalate (2 eq) at 0 ° C., then AlCl ₃ (2 eq). The reaction mixture was stirred at 0 ° C. then allowed to come to room temperature overnight. HCl (1N) was added dropwise to the reaction mixture. The crude product was extracted with EtOAc, washed with water, dried over MgSO _4, filtered, and concentrated. The crude product was then recrystallized from EtOAc / hexane to give ester XVI.

[0158]

[Chemical 50]

To a solution of ester XVI (1 eq) in EtOH was added NaOH (2.5 eq, 10 N).
Was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then heated at 45 ° C. for another 90 minutes. The product was concentrated in vacuo. The resulting residue was partitioned between EtOAc and water.
The organic layer was separated, washed with water, dried over MgSO ₄ , filtered and concentrated to give acid XVII.

[0160]

[Chemical 51]

To a solution of acid XVII (1 eq) in DMF was added benzoylpiperazine (1.2 eq) followed by DEPBT (1.2 eq) and i-Pr ₂ NEt (2 eq). The reaction mixture was stirred at room temperature for 2 hours. Then diluted with EtOAc, and washed with water and brine, dried over MgSO _4, filtered, and concentrated. The crude product was purified by flash chromatography (EtOAc / MeOH, 95: 5) to give the desired product XVIII.

[0162]

[Table 16]

[0163]

[Table 17]

[0164]

[Table 18]

[0165]

[Table 19]

[0166]   Methods for synthesizing the compounds shown in Table 6:   A. Preparation of Substituted Piperazine:   Preparation of 2-alkylpiperazine:

[0167]

[Chemical 52]

5 g of a 2-alkylpiperazine (46.3 mmol, manufactured by Piperazine Specialties) together with 500 mg of 10% palladium / activated carbon in 95% ethanol 2
It melted to 00 mL. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered off. The filtrate was concentrated to give 2-alkylpiperazine.
This required no further purification.

2-Ethylpiperazine XIX: ¹ H NMR (500 MHz, CD ₃ OD) δ
2.89 (t, J = 15.05 Hz, 1H), 2.85 (d, J = 15.11H)
z, 2H), 2.75 (t, J = 11.80 Hz, 1H), 2.65 (t, J =
11.90 Hz, 1H), 2.48 (m, 1H), 2.28 (t, J = 6.12)
Hz, 1H), 1.35 (m, 2H), 0.93 (t, J = 7.55Hz, 3H
).

[0170]

[Chemical 53]

2-Propylpiperazine XX: ¹ H NMR (300 MHz, CDCl ₃ ) δ
3.00-2.60 (m, 6H), 2.65 (t, J = 10.20Hz, 1H)
, 1.70 (m, 2H), 1.30 (m, 2H), 0.92 (t, J = 6.9H
z, 3H).

[0172]

[Chemical 54]

2-Iso-propylpiperazine XXI: ¹ H NMR (300 MHz, CDC
l ₃ ) δ3.03 to 2.30 (m, 7H), 1.50 (m, 1H), 0.91 (
dd, J = 6.60 & 6.60 Hz, 3H).

[0174]

[Chemical 55]

2-Iso-Butylpiperazine XXII: ¹ H NMR (500 MHz, CD ₃
OD) δ3.00-2.62 (m, 6H), 2.28 (t, J = 10.55Hz
, 1H), 1.68 (m, 1H), 1.38 (m, 2H), 0.92 (dd, J
= 6.65 & 6.55 Hz, 3H).

[0176]

[Chemical 56]

2-t-Butylpiperazine XXIII: ¹ H NMR (500 MHz, CD ₃
OD) δ 2.96 (d, J = 11.85 Hz, 2H), 2.80 (d, J = 12)
． 05Hz, 1H), 2.74 (t, J = 11.75Hz, 1H), 2.63 (
t, J = 11.95 Hz, 1H), 2.41 (t, J = 11.85 Hz, 1H)
, 2.31 (d, J = 13.91 Hz, 1H), 0.92 (s, 9H).

[0178]

[Chemical 57]

2-Pentylpiperazine XXIV: ¹ H NMR (500 MHz, CD ₃ OD
) Δ 2.89 (m, 2H), 2.83 (d, J = 11.95Hz, 1H), 2.
75 (t, J = 11.80 Hz, 1H), 2.65 (t, J = 11.85 Hz,
1H), 2.56 (m, 1H), 2.28 (t, J = 12.3Hz, 1H), 1
． 35 (m, 8H), 0.90 (t, J = 7.15Hz, 3H).

[0180]

[Chemical 58]

[0181]   Preparation of 2-methoxycarbonyltetrahydropiperazine XXV:

[0182]

[Chemical 59]

5 g of pyrazinecarboxylic acid methyl ester (36.2 mmol, manufactured by Lancaster) together with 500 mg of 10% palladium / activated carbon in 200 mL of 95% ethanol.
I have been The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered off. The filtrate was concentrated to give methoxycarbonyltetrahydropyrazine XXV. It was of sufficient purity for subsequent reactions.

2-Methoxycarbonyltetrahydropyrazine XXV: ¹ H NMR (300
MHz, CD ₃ OD) δ 7.10 (s, 1H), 4.84 (b, 2H), 3.6
6 (s, 3H), 3.29 (t, J = 6.0 Hz, 2H), 3.08 (t, J =
6.0 Hz, 2 H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 166.1.
130.8, 105.4, 48.4, 40.6, 40.0; MS m / z: (M +
_{^{H) + C 6 H 11 N}} 2 O 2: Calculated 143.08, Found 143.09, HPLC
Retention time 0.11 (method C).

[0185]

[Chemical 60]

[0186]   Preparation of 2-ethoxycarbonylpiperazine XXVI:

[0187]

[Chemical formula 61]

5 g of N, N′-dibenzylpiperazinecarboxylic acid ethyl ester (14.8 mmol, May Bridge, Chemical Company) was dissolved in 200 mL of 95% ethanol with 500 mg of 10% palladium / activated carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered off. The filtrate was concentrated to give 2-ethoxycarbonylpiperazine XXVI. It was of sufficient purity for subsequent reactions.

2-Ethoxycarbonylpiperazine XXVI: ¹ H NMR (300 MHz,
CD ₃ OD) δ 4.20 (q, J = 7.20 Hz, 2H), 3.46-2.60
(M, 7H), 1.27 (t, J = 6.9Hz, 3H).

[0190]

[Chemical formula 62]

[0191]   Preparation of 2-trifluoromethylpiperazine XXVII:

[0192]

[Chemical formula 63]

N, N′-Dibenzylethylenediamine (1.51 mL, 6.41 mmol)
, Methyl 3,3,3-trifluoro-2-oxopropanate (1.0 g, 6.
41 mmol) and triethylamine (1.78 mL, 12.8 mmol) in dichloromethane (100 mL) through a syringe through titanium chloride (1M CH ₂
Cl ₂ solution, 3.21 ml, 3.21 mmol) was added. The reaction mixture was stirred for 8 hours and the solvent was removed under vacuum. The residue was subjected to the next step without purification.

[0194]

[Chemical 64]

The crude product from the previous step (200 mg, 0.55 mmol or less) was treated with TFA (5
mL). Excess triethylsilane (0.88 mL, 5.5 mmol)
Was added. After 30 minutes, TFA was removed under vacuum and the residue was subjected to the next step without purification.

[0196]

[Chemical 65]

The crude product from Step 2 (0.55 mmol or less) was suspended in ether.
LiAlH ₄ (1M THF solution, 0.55 mL, 0.55 mmol) was added at room temperature. After stirring for 8 hours, the reaction mixture was quenched with saturated NaHCO ₃ solution. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO ₄ and concentrated to give a residue that was subjected to the next step without purification.

[0198]

[Chemical formula 66]

The crude product from Step 3 was treated with HO with 10% palladium / 10 mg activated carbon.
The reaction mixture dissolved in Ac (20 mL) was hydrogenated under pressure (40-50 psi) for 8 hours. The solid was filtered off. The filtrate was concentrated to give 2-trifluoromethylpiperazine XXVII as HOAc salt. It was of sufficient purity for subsequent reactions.

2-Trifluoromethylpiperazine XXVII, as HOAc (2 eq) salt: ¹ H NMR (300 MHz, CD ₃ OD) δ 3.80-2.80 (m, 7H).
, 1.95 (s, 6H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 174.
5, 53.8, 53.3, 42.7, 41.3, 40.8, 19.8; HRMS.
m / z: (M + H) ⁺ C ₅ H ₁₀ F ₃ N ₂ : calculated value 155.0796, measured value 15
5.0801.

[0201]

[Chemical formula 67]

B. Monobenzoylation of Piperazine Derivatives: Unless otherwise stated, substituted piperazines were monobenzoylated using the following procedure; Preparation of benzoylpiperazines XXVIII and XXIX:

[0203]

[Chemical 68]

A solution of substituted piperazine (1.0 g, 11.6 mmol) in a stirred solution of dry THF (50 mL) under argon with 2.5 M n-BuLi in THF (10.23 mL,
25.5 mmol) was added at room temperature. After stirring at room temperature for 1 hour, benzoyl chloride (1.27 mL, 11.0 mmol) was added to the dianion solution and another 1
Stir for 0 minutes. The reaction mixture was quenched with MeOH and the solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and saturated NaHCO ₃ . The aqueous layer was saturated with NaCl and extracted with EtOAc (2 x 30 mL). The organic layer was dried over MgSO _4, to give the crude benzoyl piperazine and concentrated. It was pure enough to be used directly without further purification. Silica gel column (EtOAc / MeOH / Et ₃ N
, 7: 3: 1) to give the purified product.

[0205]   Preparation of Benzoylpiperazine XXXIII and XLIII:

[0206]

[Chemical 69]

2-Isopropylpiperazine (1.0 g, 7.81 mmol) was maintained at room temperature under an atmosphere of argon and a 2.5 M solution of n-BuLi in THF (6.88 mL, 17) was added.
． 2 mmol) was added. After stirring at room temperature for 30 minutes, benzoyl chloride (0.86
mL, 7.42 mmol) was added and stirred for a further 10 minutes. Then MeOH was added to quench, the solvent was evaporated in vacuo and the residue was purified by silica gel flash chromatography. Elution with a mixture of EtOAc and MeOH (1: 1) gave the products XXXIII (0.62 g, 36% yield) and XLIII (0.3 g, 17% yield). Benzoylpiperazine XXXIII, XXXIV, XXXVI
, XXXVII was made using the same method as outlined above.

[0208]   Preparation of Benzoylpiperazine XXXI, XXXII: XXXIII:

[0209]

[Chemical 70]

Commercially available benzoic acid (4.8 g, 40 mmol), pentafluorophenol (7
． 4 g, 40 mmol) and EDAC (7.6 g, 40 mmol) in dry DMF
I met inside. The mixture was stirred at room temperature for 2 hours. A solution of 2-methylpiperazine (4.0 g, 40 mmol) in DMF (30 mL) was gradually added to this solution, and the mixture was stirred at room temperature for 12 hours.

DMF was evaporated, the residue was diluted with EtOAc (400 mL) and water (2 × 100
mL). The organic layer was dried over anhydrous MgSO _4, to afford the crude product concentrated in vacuo. This was EtOAc / MeOH (100: 1) then EtOAc / Me
Purification by column chromatography with OH (10: 1) gave product XX in 60% yield.

[0212]   Preparation of Benzoyl Piperazine XXX:

[0213]

[Chemical 71]

2-Methylpiperazine (10.0 g, 0.1 mol) in dry CH ₂ Cl ₂ (50
0 mL) to the stirred solution under argon at 1.0 M Me ₂ AlCl or Et ₂ AlCl
In hexane (100 ml, 0.1 mmol) and methyl benzoate (12.4 m
L, 0.1 mmol) was added at room temperature. Then, after stirring for 2 hours, NaOH (200
mL) was added. The aqueous layer was extracted with EtOAc (3 x 100 mL). Drying the combined organic layers over MgSO _4, and concentrated to give the crude product 20.0g (98%). It had a purity that could be used directly for the next reaction.

[0215]   Preparation of N-benzoyl-cis-2,6-dimethylpiperazine XLVII:

[0216]

[Chemical 72]

2,6-Dimethylpiperazine (0.82 g, 7.2 mmol) in dry THF (
50 mL) solution was kept at room temperature under argon and 2.5 M n-BuLi in THF solution (6.3 mL, 15.8 mmol) was added. After stirring for 30 minutes at room temperature, trimethylsilyl chloride (1.0 mL, 7.9 mmol) was added, and after stirring for 1 hour, benzoyl chloride (0.80 mL, 6.9 mmol) was added. After 10 minutes, the reaction mixture was quenched with MeOH and the solution was removed under vacuum. The residue is EtOAc and M
Crude by silica gel flash column chromatography eluting with a mixture of OH (1: 1) to give the product XLVII (1.48 g, 99% yield). Benzoylpiperazine XL, XLI, XLII, XLIII: XLIV, XLVI were synthesized using the same method as above.

[0218]   Preparation of Benzoyl Piperazine XXXIX:

[0219]

[Chemical formula 73]

Benzoyl chloride (3.55 mL, 29) was added to a stirred solution of 2-ethoxycarbonylpiperazine (4.6 g, 29.1 mmol) in dry methylene chloride (200 mL).
． 1 mmol) and triethylamine (2 mL) were added sequentially. After stirring for 8 hours at room temperature, saturated NaHCO ₃ solution was added and the aqueous layer was extracted with ethyl acetate (3 × 200 mL). The organic layers were combined, dried over MgSO _4, to give a crude mixture was concentrated. It contained the desired product XXXIX. This crude product was used in the next reaction without further purification.

[0221]   Preparation of Benzoylpiperazine XLVIII:

[0222]

[Chemical 74]

2-Methoxycarbonyltetrahydropyrazine (1.0 g, 7.0 mmol)
To a stirred solution of methylene chloride (50 mL) in benzoyl chloride (0.76 mL,
6.7 mmol) and triethylamine (5 mL) were added sequentially. After stirring for 8 hours at room temperature, saturated NaHCO ₃ solution was added and the aqueous layer was extracted with ethyl acetate (3 × 2 mL). The organic layers were combined, dried over MgSO ₄ and concentrated to give a crude mixture. It contained the desired product XLVII. This crude product was used in the next reaction without purification.

[0224]   Preparation of 3-hydroxymethyl-benzoylpiperazine XLIX:

[0225]

[Chemical 75]

3-Ethoxycarbonyl-benzoylpiperazine XLIX (200 mg, 0.
76 mmol) in THF (5 mL) stirred solution lithium chloride (36 mg, 0.8
4 mmol), NaBH ₄ (32 mg, 0.84 mmol) and EtOH (5 m
L) were added sequentially. After stirring for 8 hours at room temperature, it was extracted with ethyl acetate (3 × 20 mL), the organic layers were combined, dried over MgSO ₄ and concentrated to give a crude mixture. This was used in the next reaction without purification.

[0227]   Properties of monobenzoylated piperazine derivatives:

N-benzoylpiperazine XXVIII: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.37 (m, 5H), 3.73.
(Br s, 2H), 3.42 (br s, 2H), 2.85 (br s, 4H)
); ¹³ C NMR (75 MHz, CD ₃ OD) δ 170.9, 135.0, 12
9.6, 128.2, 126.5, 44.5; HRMS m / z: (M + H) ^+.
C ₁₁ H ₁₅ N ₂ O calculated value 191.1184, measured value 191.1181.

[0229]

[Chemical 76]

[0230] N- (Benzoyl) -trans-2,5-dimethylpiperazine XXIX.¹HN
MR (300MHz, CD₃ OD) δ7.50-7.28 (m, 5H), 4.3
8 (br s, 1H), 3.70 (br s, 1H), 3.40-3.20 (m
, 3H), 2.57 (dd, 1H, J = 12.96, 1.98Hz), 1.35.
(D, 3H, J = 6.87 Hz), 1.22 (d, 3H, J = 6.78 Hz); ¹³ C NMR (75 MHz, CD₃ OD) δ 171.9, 135.9, 129.
3,128.3,126.0,47.6,46.7,43.8,42.3,14
． 7, 14.3; HRMS m / z: (M + H).⁺ C₁₃H₁₉N₂ O calculated value 219
． 1497, found 219.1499.

[0231]

[Chemical 77]

N- (benzoyl) -3-methylpiperazine XXX. ¹ H NMR (300 MH
z, CD ₃ OD) δ 7.45 (m, 5H), 4.50 (d, 1H, J = 10.8)
Hz), 3.60 (b, 1H), 3.33-2.60 (m, 5H), 1.16-
0.98 (m, 3H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 170.9.
, 135.3, 129.6, 128.3, 126.5, 54.0, 50.6, 5
0.1, 45.0, 44.4, 41.7, 17.50; HRMS m / z: (M
+ H) ⁺ C ₁₂ H ₁₇ N ₂ O calculated value 205.1341, measured value 205.1336.

[0233]

[Chemical 78]

N- (benzoyl) -3-ethylpiperazine XXXI. ¹ H NMR (300M
Hz, CD ₃ OD) δ 7.47 (m, 5H), 4.55 (b, 1H), 3.64
(B, 1H), 3.36-2.59 (m, 5H), 1.51-0.82 (m, 5
H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 171.5, 135.8, 1
30.1, 128.8, 126.9, 57.2, 56.7, 52.9, 47.1
, 45.5, 42.5, 26.4, 26.0, 9.3; HRMS m / z: (M
_{^{+ H) + C 13 H 19}} N 2 O calc 219.1497, found 219.1495.

[0235]

[Chemical 79]

N- (Benzoyl) -3-propylpiperazine XXXII. ¹ H NMR (30
0 MHz, CD ₃ OD) δ7.45 (m, 5H), 4.53 (t, 1H, J = 1
3.44 Hz), 3.64 (b, 1H), 3.17-2.64 (m, 5H), 1
． 46-0.86 (m, 7H); ¹³ C NMR (75 MHz, CD ₃ OD) δ1
71.4, 135.9, 130.1, 128.8, 126.9, 55.4, 54
． 9, 53.2, 45.6, 45.0, 42.6, 35.8, 35.3, 18.
8,13.4; HRMS m / z: ( M + H) + C 14 H 21 N 2 O Calculated 233.
1654, measured value 233.1652.

[0237]

[Chemical 80]

N- (benzoyl) -3-iso-propylpiperazine XXXIII. ¹ H NM
R (300 MHz, CD ₃ OD) δ 7.45 (m, 5H), 4.30 (m, 1H)
), 3.64 (m, 1H) 3.10-2.40 (m, 5H), 1.70-0.7.
5 (m, 7H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 171.5, ¹³
5.9, 130.5, 129.3, 126.9, 61.7, 61.1, 51.2
, 45.9, 45.4, 42.5, 31.2, 30.7, 18.3; HRMSm.
/ Z: (M + H) ⁺ C ₁₄ H ₂₁ N ₂ O calculated value 233.1654, measured value 233.1
654.

[0239]

[Chemical 81]

N- (benzoyl) -3-pentylpiperazine XXXIV. ¹ H NMR (30
0 MHz, CD ₃ OD) δ7.47 (m, 5H), 4.50 (t, 1H, J = 1
7.85 Hz), 3.62 (b, 1H), 3.17-2.64 (m, 5H), 1
． 46-0.87 (m, 11H); ¹³ C NMR (75 MHz, CD ₃ OD) δ
171.4, 135.9, 130.1, 129.3, 126.8, 55.6, 5
5.2, 53.1, 45.6, 45.0, 42.5, 33.6, 33.0, 32
． 0, 28.9, 25.9, 25.3, 22.6, 13.4; HRMS m / z.
: (M + H) ⁺ C ₁₆ H ₂₅ N ₂ O calculated value 261.1967, measured value 261.196
9.

[0241]

[Chemical formula 82]

N- (benzoyl) -3-iso-butylpiperazine XXXV. MS m / z :(
M + H) ⁺ C ₁₅ H ₂₃ N ₂ O: calculated 247.18, found 247.22. HPL
C holding time: 1.04 minutes (method C).

[0243]

[Chemical 83]

N- (benzoyl) -3-t-butylpiperazine XXXVI. ¹ H NMR (3
00 MHz, CD ₃ OD) δ7.45 (m, 5H), 4.70 (m, 1H), 3
． 66 (m, 1H), 3.17-2.43 (m, 5H), 1.17-0.84 (
m, 9H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 171.6, 135.
9, 131.0, 129.4, 126.9, 65.3, 64.6, 49.6, 4
6.5, 45.9, 43.7, 42.3, 32.7, 25.7; HRMS m /
z: (M + H) ⁺ C ₁₅ H ₂₃ N ₂ O calculated value 247.1810, measured value 247.18
15.

[0245]

[Chemical 84]

N- (Benzoyl) -cis-3,5-di-methylpiperazine XXXVII. ¹ H
NMR (300 MHz, CD ₃ OD) δ 7.43 (m, 5H), 4.55 (d
, 1H, J = 12.0 Hz), 3.55 (d, 1H, J = 9.60 Hz), 2.
74-2.38 (m, 5H), 1.13-0.94 (m, 6H); ¹³ C NMR.
(75 MHz, CD ₃ OD) δ 170.5, 135.5, 129.6, 128.
3, 126.6, 53.4, 50.9, 50.2, 17.7, 17.3; HRM
S m / z: (M + H) ⁺ C ₁₃ H ₁₉ N ₂ O calculated value 219.1497, found 21
9.1492.

[0247]

[Chemical 85]

N- (benzoyl) -3-trifluoromethylpiperazine XXXVIII. MS
m / z: (M + H) ⁺ C ₁₂ H ₁₄ F ₃ N ₂ O: calculated value 259.11, measured value 25
9.05. HPLC retention time: 0.65 minutes (method A).

[0249]

[Chemical 86]

N- (benzoyl) -3-ethoxycarbonylpiperazine XXXIX. MS m
/ Z: (M + H) ⁺ C ₁₄ H ₁₉ N ₂ O ₃ : calculated value 263.14, measured value 263.2.
0. HPLC retention time: 0.80 minutes (method C).

[0251]

[Chemical 87]

N- (benzoyl) -2-methylpiperazine XL. ¹ H NMR (300 MHz
, CD ₃ OD) δ 7.47 (m, 5H), 3.30-2.70 (m, 7H), 1
． 36 (d, 3H, J = 6.90 Hz); ¹³ C NMR (75 MHz, CD ₃ O
D) δ170.0, 135.4, 129.7, 128.5, 126.3, 48.
5, 44.3, 14.5; HRMS m / z: (M + H) ⁺ C ₁₂ H ₁₇ N ₂ O calculated 205.1341, found 205.1341.

[0253]

[Chemical 88]

N- (benzoyl) -2-ethylpiperazine XLI. ¹ H NMR (300 MH
z, CD ₃ OD) δ 7.49 (m, 5H), 3.34-2.80 (m, 7H),
2.10-1.70 (m, 2H), 0.85 (b, 3H); ¹³ C NMR (75
MHz, CD ₃ OD) δ 171.5, 135.1, 129.8, 128.5, 1
26.5, 48.5, 46.0, 43.9, 21.8, 9.6; HRMS m /
z: (M + H) ⁺ C ₁₃ H ₁₉ N ₂ O calculated value 219.1497, found value 219.15
01.

[0255]

[Chemical 89]

N- (benzoyl) -2-propylpiperazine XLII. ¹ H NMR (300
MHz, CD ₃ OD) 7.50 (m, 5H), 3.60-2.80 (m, 7H)
), 2.10-0.70 (m, 7H); ¹³ C NMR (75 MHz, CD ₃ OD
) Δ172.5, 135.0, 129.9, 128.6, 126.7, 48.7
, 46.2, 43.8, 30.9, 18.9, 13.1; HRMS m / z: (
M + H) ⁺ C ₁₄ H ₂₁ N ₂ O calculated 233.1654, found 233.1650.

[0257]

[Chemical 90]

N- (benzoyl) -2-iso-propylpiperazine XLIII. ¹ NMR (3
00 MHz, CD ₃ OD) δ 7.50 (b, 5H), 4.40 (m, 1H), 3
． 60-2.50 (m, 6H), 1.10-0.70 (m, 7H); ¹³ C NM.
R (75MHz, CD ₃ OD) δ171.1, 135.0, 130.0, 128
． 7, 127.0, 60.6, 54.1, 43.9, 42.3, 25.4, 19
． 3,18.4; HRMS m / z: (M + H) ⁺ C ₁₄ H ₂₁ N ₂ O calculated 233.
． 1654, found 233.1653.

[0259]

[Chemical Formula 91]

N- (benzoyl) -2-pentylpiperazine XLIV. ¹ H NMR (300
MHz, CD ₃ OD) δ 7.47 (b, 5H), 3.40-2.80 (m, 7H
), 2.10-0.70 (m, 11H); ¹³ C NMR (75 MHz, CD ₃ O
D) δ 171.2, 135.0, 129.9, 128.6, 126.7, 48.
7, 46.2, 43.8, 31.0, 28.8, 25.3, 22.2, 13.4
HRMS m / z: (M + H) ⁺ C ₁₆ H ₂₅ N ₂ O calculated value 261.1967, measured value 261.1970.

[0261]

[Chemical Formula 92]

N- (benzoyl) -2-iso-butylpiperazine XLV. MS m / z: (M
+ H) ⁺ C ₁₅ H ₂₃ N ₂ O: calculated value 247.18, measured value 247.23. HPLC
Retention time: 1.06 minutes (method C).

[0263]

[Chemical formula 93]

N- (benzoyl) -2-t-butylpiperazine XLVI. ¹ H NMR (30
0 MHz, CD ₃ OD) δ7.45 (m, 5H), 4.53 (t, 1H, J = 5
． 70 Hz), 3.60-2.60 (m, 6H), 1.14 (s, 9H); ¹³ C
NMR (75 MHz, CD ₃ OD) δ173.5, 136.7, 129.9,
128.9, 126.6, 55.9, 44.8, 44.5, 42.7, 36.5
, 27.8; HRMS m / z: (M + H) + C 15 H 23 N 2 O calc 247.1
810, measured value 247.1808.

[0265]

[Chemical 94]

N- (benzoyl) -cis-2,6-dimethylpiperazine XLVII. ¹ H N
MR (300 MHz, CD ₃ OD) δ7.45 (m, 5H), 4.18 (b, 2)
H), 2.85 (m, 4H), 1.33 (d, 6H, J = 6.90Hz); ¹³ C
NMR (75 MHz, CD ₃ OD) δ172.0, 136.7, 128.9,
128.3, 125.8, 49.1, 47.1, 19.2; HRMS m / z:
(M + H) ⁺ C ₁₃ H ₁₉ N ₂ O calculated value 219.1497, measured value 219.1491.
．

[0267]

[Chemical 95]

N- (benzoyl) -3-methoxycarbonyltetrahydropiperazine XLVI
II. MS m / z: (M + H) + C 13 H 15 N 2 O 3: Calculated 247.11, Found 247.13. HPLC retention time: 1.00 minutes (method C).

[0269]

[Chemical 96]

3-Hydroxymethylbenzoylpiperazine XLIX. MS m / z: (M + H
) ⁺ C ₁₂ H ₁₇ N ₂ O ₂ : calculated value 221.13, measured value 221.17. HPLC retention time: 0.32 minutes (method C).

[0271]

[Chemical 97]

[0272]   C. Coupling of monobenzoylpiperazine with glyoxyl chloride:

[0273]

[Chemical 98]

To a solution of indole glyoxoyl V (1 eq) in dry CH ₂ Cl ₂ was added saturated benzoylpiperazine (1 eq) at room temperature. The mixture was cooled to 0 ° C. and diisopropylamine (1.3 eq) was added dropwise. After 5 minutes, the reaction mixture was warmed to room temperature and shaken for 3 hours. The crude crude product XL was purified by preparative HPLC. The characteristics are shown in Table 6.

Preparation of N- (benzoyl) -3-hydroxymethyl-N ′-[(7-methoxycarbonyl-indol-3-yl) -oxyacetyl] -piperazine [Example 98]:

[0276]

[Chemical 99]

3-Hydroxyethyl-benzoylpiperazine XLIX (8.0 mg, 0.0
BSTFA (8.1 mg) to a stirred solution of 36 mmol) in acetonitrile (5 mL).
, 0.036 mmol) was added. After stirring for 30 minutes at room temperature, (7-methoxycarbonyl-indol-3-yl) -oxoacetyl chloride (8.1 mg, 0.
(036 mmol) and pyridine (0.5 mL) were added. Further, the mixture was stirred at room temperature for 2 hours. Concentrate in vacuo and purify the residue on a Shimadzu HPLC purification system to N- (benzoyl) -3-hydroxymethyl-N ′-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine [. Example 98] 2 mg was obtained.

[0278]   D. Hydrolysis of ester groups to acid groups:

N- (benzoyl) -3-hydroxycarbonyl-N ′-[(4-fluoro-
Preparation of indole-3-yl) -oxoacetyl] -piperazine [Example 101]:

[0280]

[Chemical 100]

N- (Benzoyl) -3-ethoxycarbonyl-N ′-[(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (10 mg, 0.02 mmol) in methanol (1 mL) and water. (1 mL) stirred solution with potassium carbonate (9
mg, 0.06 mmol) was added. After stirring at room temperature for 8 hours, the product was concentrated in vacuo to obtain a purified product. This was purified by preparative HPLC and N- (benzoyl) -3-
2 mg of hydroxycarbonyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine [Example 101] was obtained.

Preparation of N- (benzoyl) -3- (R) -methyl-N ′-[(7-hydroxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine [Example 137]:

[0283]

[Chemical 101]

N- (benzoyl) -3- (R) -methyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (20 mg, 0.
0.5 mL of water was added to a solution of (05 mmol) dissolved in methanol containing 0.5 N sodium methoxide (5 mL). After stirring at room temperature for 8 hours, 10% HCl was added to the reaction mixture to adjust the pH to 6. The product that precipitated from the solution was filtered off and N- (benzoyl) -3- (R) -methyl-N '-[(7-hydroxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine [Example 137]. ]

[0285]

[Table 20]

[0286]

[Table 21]

[0287]

[Table 22]

[0288]

[Table 23]

[0289]

[Table 24]

[0290]

[Table 25]

((Note) In Table 6 and other tables, the superscript symbols “A”, “
B "or" C "indicates the HPLC method used (i.e. indicates Method A, B or C, respectively). Production method of Examples 148-194 shown in Table 7:

[0292]

[Chemical 102]

Substituted indole-3-glyoxylyl chloride V (in room temperature CH ₂ Cl ₂
To 1 equivalent) tert-butyl 1-piperazinecarboxylate (1 equivalent) and diisopropylethylamine (1.5 equivalent) were added. Stir this solution for 2 hours at room temperature,
After the stirring, LC / MC analysis confirmed the reaction was complete. The solvent was removed under reduced pressure and the resulting residue was diluted with ethyl acetate (250 ml) and diethyl ether (250 ml). Then washed organic solution with water (100 ml × 3) and brine (50ml), dried over MgSO _4, and b filtered and concentrated. To the pale yellow solid was added 30 ml of 20% trifluoroacetic acid in CH ₂ Cl ₂ . The solution was concentrated and dried under reduced pressure to give the desired product VII. LC / M
S analysis confirmed that the product was 100% pure. This product was used in the next step without further purification.

[0294]

[Chemical 103]

Piperazine indole-3-glyoxylamine (1 equivalent) was bound to the resin 1- (
3-Dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) (7
Eq.) And carboxylic acid of dichloroethane (DCE) or DMF (dimethylformamide) (2 eq.), Where the carboxylic acid is not dissolved in DCE. The reaction was shaken at room temperature for 12 hours. The product XLI was filtered and concentrated. The product with a purity of less than 70% was diluted with methanol and purified using Shimadzu's automated preparative or conditioned HPLC system.

[0296]   Production of Example 195 in Table 7.

[0297]

[Chemical 104]

Tertiary butyl-1-piperazinecarboxylate (601 mg, 3.23 ml) and 4-acid imidazole imidazole (33 mg, 2.9) in dichloromethane (30 ml).
4 mmol) in a solution of DMAP (394 mg, 3.22 mmol) and EDC (
616 mg, 3.22 mmol) was added. The reaction mixture was stirred at room temperature for 21.5 hours. The solvent was removed under reduced pressure to give a white solid. Gradient elution of this solid (
2% 100% EtOAc ~5% MeOH / EtOAc , 1/5 / 95NH 3
Flash chromatography with (sat. Aq.) / MeOH / EtOAc) gave XLII as a white solid.

[0299]

[Chemical 105]

Compound XXII (130 mg, 0.464 mmol) was added to dioxane (4M, 5
HCI in (ml) was added. The mixture was stirred at room temperature for 3 hours. The excess reagent was removed under reduced pressure to give hydrochloride salt XLIII as a white solid (100% conversion).

[0301]

[Chemical formula 106]

4-Fluoroindole glyoxyl chloride was prepared as described above in XLIII.
I was allowed to couple.

[0303]

[Table 26]

[0304]

[Table 27]

[0305]

[Table 28]

[0306]   Synthesis of Examples 195-215 in Table 8.

[0307]

[Chemical formula 107]

Pentafluorophenyl (1.84 g, 10 mmol) in DMF (15 mL)
) To picolinic acid (1.23 g, 10 mmol) and EDC (1.91 g, 10 m)
mol) was added at room temperature over 4 hours. The crude product XLIV was diluted with CH ₂ Cl ₂ and washed with water, 0.1M HCl and brine. The organic phase was dried over MgSO _4, filtered, and concentrated. The crude material was used without further purification.

[0309]

[Chemical 108]

(R) -Methylpierazine (1.0 g, 10 m) in DMF (20 mL) at room temperature.
to a solution of picolinic acid pentafluorophenyl ester XLIV in DMF (20 ml) was added slowly. The product was diluted with CH ₂ Cl ₂ ,
Then washed with water and brine, dried over MgSO ₄ , filtered and concentrated. The product XLV was then flash chromatographed (100% EtOAc-5
Purified by 0% MeOH / EtOAc).

Piperazine XLVI was prepared using a method compilation similar to the method outlined in steps A and B above.

[0312]

[Chemical 109]

Indole glyoxyl chloride V (1 equivalent) and 3- (R)-in THF
Diisopyropyrethylamine (1.5 eq) was added dropwise at 0 ° C. to a mixture of methyl-1-piperazine carboroxylate XLV or XLVI (1 eq). The solution was stirred at room temperature for a further 2 hours and the resulting crude compound was taken up in preparative or preparative H
Purified by PLC.

[0314]

[Table 29]

[0315]

[Table 30]

Further Analytical Data for Selected Compounds 1- (4-Methylbenzoyl) -4-[(1H-indol-3-yl) oxoacetyl] piprazine (Example 15)

[0317]

[Chemical 110]

MS (ESI): 376 (M + H) ⁺ ; IR (KBr): 3150, 3140, 2922, 2868, 1780, 162
9,1519,1433,1272,1158,1006,829,775,7
53,645 cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ 2.40 (s, 3H), 3.60-3.79 (m
, 8H), 7.23-7.45 (m, 7H), 7.99 (d, J = 3.1 Hz).
, 1H), 8.34 (m, 1H), 9.10 (s, 1H).

1- (Benzoyl) -4 [(1H-4-fluoroindol-3-yl) oxoacetyl] piperazine (Example 19)

[0320]

[Chemical 111]

MS (ESI): 380 (M + H) ⁺ HRMS calcd for C ₂₁ H ₁₈ FN ₃ O ₃ [(M + H)] ⁺ , 380.
, 14105; found, 380, 1412. ¹ H-NMR (DMF-d7) δ 12.71 (s, 1H), 8.02 (s, 1H)
), 7.46-7.56 (m, 6H), 7.31 (ddd, J = 4.71, 7 ,.
99 Hz, 1H), 7.03 (dd, J = 7.84, 10.98 Hz, 1H
), 3.77 (br.s, 4H), 3.57 (br.s, 4H).

1- (Benzoyl) -4-[(1H-4-chloroindol-3-yl) oxoacetyl] pepyrazine (Example 20)

[0323]

[Chemical 112]

MS (ESI): 396 (M + H) ⁺ HRMS calcd for C ₂₁ H ₁₈ ClN ₃ O ₃ [(M + H)] ⁺ , 39
6.11150; found, 396.1105. ¹ H NMR (DMF-d7) δ 12.74 (br, s, 1 H), 8.03 (s
, 1H), 7.57-7.65 (m, 1H), 7.50 (s, 5H), 7.28.
-7.38 (m, 1H), 3.42-3.83 (m, 8H).

1- (Benzoyl) -4-[(1H-6-fluoroindol-3-yl) oxoacetyl] piperazine (Example 28)

[0326]

[Chemical 113]

MS (ESI): 380 (M + H) ⁺ HRMS calcd for C ₂₁ H ₁₈ FN ₃ O ₃ [(M + H)] ⁺ , 380.
． 14105; found, 380.1414. 1H NMR (DMF-d7) δ 12.09 (s, 1H), 7.81 (dd, J
= 5.64, 8.46 Hz, 1H), 7.62 (s, 1H), 7.08 (s,
5H), 7.01 (dd, J = 2.28, 9.61 Hz, 1H), 2.86-
3.52 (m, 8H). Anal. _{Calcd for C 21 H 18 FN 3} O 3: C, 66.48; H, 4
． 78, N, 11.08. Found: C, 66.09, H, 4.78, N, 1
0.94.

1- (Benzoyl) -4-[(1H-4,6-difluoroindol-3-yl) oxoacetyl] piperazine (Example 42)

[0329]

[Chemical 114]

¹ H NMR (DMSO-d ₆ ) δ 3.40 (br s, 4 H), 3.65 (b
rs, 4H), 7.06 (t, 1H), 7.20 (d, J = 8.49 Hz,
1H), 8.27 (s, 1H), 12.65 (br s, 1H). _{C 21 H 17 F 2 N 3} O 3 /0.322H 2 O: Calculated analysis for: C, 6
2.57; H, 4.41; N, 10.42. Found: C, 62.56; H, 4.
46; N, 10.11.

[0331]

[Chemical 115]

¹ H NMR (DMSO-d ₆ ) δ 3.40 (br s, 4H), 3.67 (b
rs, 4H), 7.43 (br s, 5H), 7.54 (dd, J = 2.25)
, 8.97 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 8.2
9 (s, 1H), 12.79 (br s, 1H). _{C 21 H 17 N 3 BrF O} 3 · 1.2H 2 O Calculated analysis for: C, 52
． 56; H, 4.07; N, 8.76. Found: C, 52.33; H, 3.69.
N, 8.50.

1- (Benzoyl) -4-[(1H-4-fluoro-7-trifluoroethoxyindol-3-yl) oxoacetyl] piperazine (Example 51)

[0334]

[Chemical formula 116]

¹ H NMR (DMSO-d ₆ ) δ 3.61 (br m, 4H), 3.80 (b
rm, 4H), 4.52 (m, 2H), 6.68 (m, 1H), 6.91 (m
, 1H), 7.45 (s, 5H), 8.07 (d, J = 2.91 Hz, 1H)
, 9.37 (s, 1H). _{C 23 H 19 F 4 N 3} O 4 · 0.59H 2 O, calculated analytical values for the 0.47- ethyl acetate: C, 56.44; H, 4.56 ; N, = 7.94. Measured value: C, 5
6.44; H, 4.16; N, = 8.19.

1- (benzoyl) -4-[(1H-4-bromo-7-fluoroindole-
3-yl) oxoacetyl] piperazine (Example 55)

[0337]

[Chemical 117]

¹ H NMR (CDCl ₃ ) δ3.6-3.9 (br m, 8H), 6.92 (
t, 1H), 7.42 (br s, 6H), 8.09 (s, 1H), 9.5 (b
rs, 1H). _{C 21 H 17 BrFN 3 O 3} · 0.25H 2 O, calculated analytical values for 0.21 ethyl acetate: C, 54.5; H, 4.02 ; N, 16.6. Found: C, 54.50; H, 4.09; N5 8.44.

[0339]   Example 90

[0340]

[Chemical 118]

¹ H NMR: (DMSO-d ₆ ) d3.66 (br.s, 4H), 7.27 (
t, J = 8.31 Hz, 1H), 7.43 (br.s, 7H), 8.01 (m
, 1H), 8.14 (s, 1H), 10.14 (s, 1H), 12.42 (br
． s, 1H) MS: (M + H) ⁺ 480.00, (MH) 406.02 IR: 1636, 1592 cm ^-1.

N- (Benzoyl)-(R) -3-methyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (Example 93)

[0343]

[Chemical formula 119]

¹ H NMR (300 MHz, CD ₃ OD) δ 8.20 (s, 0.5H), 8
． 15 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.
00 (m, 7H), 1.30 (b, 3H). C ₂₂ H ₂₁ FN ₃ O ₃ calculated for ^{MS m / z: (M +} H) +: 394.16; Found 394.23, HPL
C holding time: 0.92 minutes (method B).

N- (Benzoyl)-(S) -3-methyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (Example 94)

[0346]

[Chemical 120]

¹ H NMR (300 MHz, CD ₃ OD) δ 8.20 (s, 0.5H), 8
． 13 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.
00 (m, 7H), 1.30 (b, 3H). C ₂₂ H ₂₁ FN ₃ O ₃ calculated for ^{MS m / z: (M +} H) +: 394.16; Found 394.25. HPL
C holding time: 1.32 minutes (method A).

N- (benzoyl) -2-methyl-N ′-[(4-fluoro-indole-3
-Yl) -oxoacetyl] -piperazine (Example 95)

[0349]

[Chemical 121]

¹ H NMR (300 MHz, CD ₃ OD) δ8.20 (s, 0.5H), 8
． 13 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.
00 (m, 7H), 1.37 (d, J = 6.78Hz, 1.5H), 1.27 (
d, J = 6.84 Hz, 1.5H). M calculated for C ₂₂ H ₂₁ FN ₃ O ₃
S m / z: (M + H) ⁺ : 394.16: found 394.23. HPLC retention time: 1.32 minutes (method A).

N- (Benzoyl) -3-hydroxylmethyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] piperazine (Example 99)

[0352]

[Chemical formula 122]

[0353]¹  1 H NMR (300 MHz, CD₃ OD) δ 7.50 (b, 5H), 7.3
9-6.72 (m, 4H), 5.00-2.80 (m, 9H). C_{twenty two}H₂₀FN ₃  NaO_Four MS m / z calculated for: (M + Na)⁺ : 432.13:
Found 432.19, HPLC retention time: 1.23 minutes (Method A).

N- (Benzoyl)-(R) -3-methyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 102)

[0355]

[Chemical 123]

¹ H NMR (300 MHz, CD ₃ OD) 8.50 (d, J = 6.48 Hz)
, 1H), 8.15 (s, 0.5H), 8.10 (s, 0.5H), 8.00
(D, J = 7.38 Hz, 1H), 7.42 (m, 6H), 5.00-3.00
(M, 7H), 4.02 (s, 3H), 1.34 (b, 3H); ¹³ C NMR (
75 MHz, CD ₃ OD) δ 186.2, 166.9, 137.9, 135.3, 130.3, 128.8
, 127.2, 126.9, 126.4, 122.7, 114.5, 114.
0, 51.6, 5.7, 45.6, 15.4, 14.2. C ₂₄ H ₂₄ N ₃ O ₅ calculated for ^{MS m / z: (M +} H) +: 434.17: Found 434.2
4, HPLC retention time: 1.41 minutes (method B).

N- (benzoyl) -3-hydroxylmethyl-N ′-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 98
)

[0358]

[Chemical formula 124]

¹ H NMR (300 MHz, CD ₃ OD) δ 8.54 (b, 1H), 8.2
4 (s, 0.5H), 8.16 (s, 0.5H), 8.00 (m, 1H), 7
． 47 (m, 6H), 5.00-3.00 (m, 9H), 4.02 (s, 3H)
． C ₂₄ H ₂₄ N ₃ MS calculated for _{O 6 m / z: (M} + H) +: 450.
17; measured value 450.24. HPLC retention time: 1.44 minutes (method A).

N- (Benzoyl) -2-methoxycarbonyl-N ′-[(7-methoxycarbonyl-indol-3-yl) -oxo-acetyl] -tetrahydropyrazine (Example 121)

[0361]

[Chemical 125]

¹ H NMR (500 MHz, CD ₃ OD) δ 8.50 (m, 1H), 8.2
1 (s, 1H), 7.93 (m, 1H), 7.44 (m, 7H), 4.00 (
s, 6H), 4.00-3.30 (m, 4H); ¹³ C NMR (125 MHz
, CD ₃ OD) δ 184.7, 167.9, 166.1, 165.3, 165.
1, 164.9, 140.2, 137.2, 132.5, 129.6, 128.
3, 128.2, 127.6, 125.1, 123.9, 116.0, 115.
6, 115.0, 52.8, 52.6, 47.0, 43.8. C ₂₅ H ₂₂ N ₃ O ₇
MS m / z: (M + H) ⁺ : 476.15; found 476.
． 21. HPLC retention time: 1.62 minutes (method A).

N- (Benzoyl) -2-propyl-N ′-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 126)

[0364]

[Chemical formula 126]

[0365]¹  1 H NMR (300 MHz, CD₃ OD) δ 8.50 (d, J = 6.93H
z, 1H), 8.17 (s, 0.5H), 8.08 (s, 0.5H), 7.9
8 (d, J = 6.00 Hz, 1H), 7.45 (m, 6H), 5.00-2.9
0 (m, 7H) 4.02 (s, 3H), 1.70-0.60 (m, 7H);¹³C
  NMR (75 MHz, CD₃ OD) δ 186.0, 167.6, 166.9.
, 138.0, 136.1, 135.8, 130.2, 128.9, 127.2.
, 126.9, 126.4, 122.7, 114.5, 114.1, 51.7,
46.2, 44.0, 41.3, 31.5, 19.2, 13.2, 12.9. C ₂₆ H₂₈N₃ O_Five MS m / z calculated for: (M + H)⁺ : 462.20;
Found 462.30. HPLC retention time: 1.69 minutes (method A).

N- (benzoyl)-(R) -3-methyl-N '-[(7-hydroxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 137)
)

[0367]

[Chemical 127]

¹ H NMR (300 MHz, CD ₃ OD) δ 8.46 (b, 1H), 8.1
4 (s, 0.5H), 8.09 (s, 0.5H), 8.00 (d, J = 7.1)
7 Hz, 1H), 7.43 (m, 6H), 5.00-2.90 (m, 7H), 1
． 32 (b, 3H); ¹³ C NMR (75 MHz, CD ₃ OD) δ186.3.
, 168.2, 167.1, 137.8, 135.3, 130.3, 128.8
, 127.1, 126.9, 126.7, 122.7, 115.4, 113.9.
, 50.7, 45.6, 15.4, 14.2. C ₂₇ H ₃₀ N ₃ O ₅ calculated for ^{MS m / z: (M +} H) +: 420.16; Found 420.16. HPLC
Retention time: 1.43 minutes (method A).

N- (Benzoyl) -3-trifluoromethyl-N ′-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] piperazine (Example 142)
)

[0370]

[Chemical 128]

[0371]¹  1 H NMR (300 MHz, CD₃ OD) δ 8.52 (b, 1H), 8.0
3 (s, 1H), 8.02 (d, J = 7.56Hz, 1H), 7.45 (m,
6H), 5.00-3.00 (m, 7H), 4.03 (s, 3H). C_{twenty four}H_{twenty one}F ₃  N₃ O_Five MS m / z calculated for: (M + H)⁺ : 488.14; actual measurement
Value 488.15. HPLC retention time: 1.65 minutes (method A).

N- (Benzoyl) -3-trifluoromethyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (Example 143)

[0373]

[Chemical formula 129]

[0374]¹  1 H NMR (300 MHz, CD₃ OD) δ 8.11 (s, 1H), 7.5
0-6.90 (m, 9H), 5.00-3.00 (m, 7H). C_{twenty four}H_{twenty one}F₃ N ₃  O_Five MS m / z calculated for: (M + H)⁺ : 488.14; measured value 4
88.12. HPLC retention time: 1.42 minutes (method A).

N- (Benzoyl)-(R) -3-methyl-N '-[(4-fluoro-7-bromoindol-3-yl) -oxoacetyl] -piperazine (Example 144)

[0376]

[Chemical 130]

¹ H NMR (CDCl ₃ ) d 1.31 (br.s, 3H), 3.34 (br
． s, 4H), 3.59 (br.s, 3H), 6.90 (t, J = 8.7 Hz)
, 1H), 7.38 (br.s, 6H), 8.05 (br.s, 1H), 9.4.
6 (br.s, 1H) MS: (M + H) ⁺ 473.80, (M−H) 470.02 IR: 1634, 1579 cm ⁻¹ C22H19N3O3BrF. Analytical value C, 54 calculated for 0.6H ₂ O
． 68; H, 4.21; N, 8.7. Found C, 54.46; H, 4.14; N.
, 8.56.

1-[(pyrid-2-yl) oxo] -4-[(IH-4-fluoro-indol-3-yl) oxoacetyl] piperazine (Example 166)

[0379]

[Chemical 131]

MS (ESI): 381 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 3.56 (m, 2H), 3.66 (m, 2H),
3.82-3.94 (m, 4H), 6.97 (m, 1H), 7.33 (m, 2H)
), 7.57 (m, 1H), 7.70 (m, 1H), 8.01 (m, 1H), 8
． 20 (s, 1H), 8.66 (m, 1H).

1-[(pyrid-2-yl) oxo] -4-[(IH-4,7-difluoro-indol-3-yl) oxoacetyl] piperazine (Example 191)

[0382]

[Chemical 132]

MS (ESI): 413 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ3.54-3.65 (m, 4H), 3.76-3.
． 93 (m, 4H), 6.95 (m, 2H), 7.52 (m, 1H), 7.66
(M, 1H), 7.96 (m, 1H), 8.20 (m, 1H), 8.60 (m,
1H).

[0384] Implementation 195

[0385]

[Chemical 133]

MS (ESI): 370 (M + H) ^{+ 1} H NMR: (CD ₃ OD, δ = 3.30 ppm) 8.82 (s, 1H), 8
． 21 (s, 1H), 8.00 (s, 1H), 7.37-7.26 (m, 2H)
, 7.02-6.96 (m, 1H), 3.97 (bs, 2H), 3.86 (a
pp dd, J = 6.4, 3.3, 4H), 3.64 (app, dd, J = 6.
3, 4.0, 2H); LC / MS: (ES +) m / z (M + H) ⁺ = 370, analytical HPLC (Rt = 0.810 min) Purity: 100%

[0387]   Example 212

[0388]

[Chemical 134]

MS (ESI): 402 (M + H) ^{+ 1} H NMR: (CD ₃ OD, δ = 3.30 ppm) 8.65-8.51 (m,
2H), 8.24-8.19 (m, 1H), 8.02-7.94 (m, 1H),
7.73-6.68 (m, 2H), 7.56-7.39 (m, 2H), 4.63
-3.09 (b m, 7H), 1.35 (m, 3H)

Methods for making compounds of Formula I are shown in Schemes 14-22 and further illustrated in Tables 14-18.

[0391]

[Chemical 135]

The starting indole 1 (Scheme 14) is well known and is described in Gribble, G
It is easily manufactured according to methods described in the literature, such as the method described in (Reference 24) or Bartoli et al. (Reference 36). Indole 1 is treated with oxalyl chloride in THF (tetrahydrofuran) or ether according to methods described in the literature (Lingens, F. et al., Reference 25) to give the desired glyoxyl chloride 2. The intermediate glyoxyl chloride 2 was then coupled under basic conditions with benzoylpiperazine 3 (Desai, M. et al., Ref. 26) to give 4.

[0393]

[Chemical 136]

Indole glyoxamide 4 (Scheme 15) was treated under basic conditions (BEMP or N
Treatment with an alkylating agent (R ₄₀ X) under aH) gave the N-alkylated derivative 5.

[0395]

[Chemical 137]

N-acyl derivative 6 is prepared by treating indole glyoxamide 4 with an acid chloride (R ₄₀ aCOCl) in the presence of i-Pr ₂ NEt (Scheme 16). Alternatively, the bis-acylated product is prepared as shown in Scheme 17.

[0397]

[Chemical 138]

Indole-3-glyoxyl chloride 2 (Scheme 17) was converted to tert-butyl 1
-Treatment with piperazinecarboxylate 7 gave the coupling product 8. Bo
Removal of the c protecting group is carried out with 20% TFA / CH ₂ Cl ₂ . This product is then coupled with the acid chloride (R ₄₀ cCOCl) to give the bis-acyl product 10.

[0399]

[Chemical 139]

Carbamate 11 is synthesized by reacting indole glyoxamide 4 with chloroformate (R ₄₀ dOCOCl) in the presence of i-Pr ₂ NEt or NaH (
Scheme 18).

[0401]

[Chemical 140]

Urea is made in three ways. Treatment of indole glyoxamide with carbamoyl chloride (RaRbNCOCl) in the presence of i-Pr ₂ NEt is desirable for urea 1.
Gives 2 (Scheme 19).

[0403]

[Chemical 141]

Alternatively, 4 (Scheme 20) is treated with P-nitrophenyl chloroformate and i-Pr ₂ NEt to give P-nitrophenyl carbamate 13 which is exposed to the amine (RaRbNH) to give the desired product. Urea 14 was obtained.

[0405]

[Chemical 142]

Finally, reaction of indolecryoxamide 4 with isocyanate (RaNCO) in the presence of i-Pr ₂ NEt yields urea 15 (Scheme 21).

[0407]

[Chemical 143]

Indole sulfonamide 15 (Scheme 22) is readily prepared by treating indole glyoxamide 4 with a sulfonyl chloride (RaSO ₂ Cl) in the presence of i-Pr ₂ NEt.

[0409]

[Table 31]

[0410]

[Table 32]

[0411]

[Table 33]

[0412]

[Table 34]

[0413]

[Table 35]

[0414]

[Table 36]

[0415]

[Table 37]

[0416]

[Table 38]

[0417]

[Table 39]

[0418]   Experiment   3) General method for making Examples 1-34.

[0419]

[Chemical 144]

Oxalyl chloride (1.2 eq) was added dropwise at 0 ° C. to a solution of substituted indole IV (1 eq) in dry Et ₂ O. After 5 minutes, the reaction mixture was warmed to room temperature. Or if necessary, heated to ~ 35 ° C overnight. The solid substituted intermediate indole-3-glyoxyl chloride V formed was filtered through dry ether (2 x 1 m).
It was washed with 1) to remove excess oxalyl chloride. The product was then dried under reduced pressure to give the desired glyoxyl chloride V.

If the reaction in Et ₂ O was unsuccessful, the following method was adopted. Dry T
Oxalyl chloride (1.2 eq) was added dropwise to a solution of substituted indole IV (1 eq) in HF (tetrahydrofuran) solvent. After 5 minutes, the reaction was warmed to room temperature or heated to ~ 70 ° C under nitrogen if necessary. After concentration under reduced pressure, the resulting crude intermediate V was provided to the next step without further purification.

[0422]

[Chemical 145]

To a solution of indole glyoxyl chloride V (1 eq) in dry THF was added benzoylpiperazine (1 eq) at room temperature. The mixture was then cooled to 0 ° C. before diisopropylamine (1.3 eq) was added dropwise. 5 minutes later,
The reaction mixture was warmed to room temperature and shaken for 3 hours. The resulting crude product was purified by preparative HPLC and obtained the properties as shown in Table 14.

[0424]

[Chemical 146]

Indole glyoxamide VIa (0.0
416 μM), alkyl or aryl halide, R ₂ X (0.0478 μM),
Dry DMF (2 ml) and BEMP (0.0541 μM) were added at room temperature. The reaction was shaken in a heating block under nitrogen at a temperature of 70-80 ° C. for 4 hours. After evaporation of the solvent under reduced pressure, the purified compound was purified by preparative HPLC, Table 1
The characteristics shown in FIG.

For Examples 33 and 34, the reactions were run in NMP and heated at 80 ° C. for 16 hours before purification by preparative HPLC.

[0427]   Manufacturing of implementation 19

[0428]

[Chemical 147]

Indole glyoxamide VIId (200 m in THF (1 mL) in a sealed tube.
g, 0.5 mmol) to BEMP (0.2 equivalent) and t-butyl acrylate (
0.37 ml, 2.5 mmol) was added. The reaction mixture was heated to 90 ° C. overnight. The crude product was poured into 1M HCl and extracted with EtOAc. The organic phase was washed with brine NaCl, dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (2: 1 EtOAc / hexane) to give 195 mg of alkylated product 19.

[0430]   Production of Example 21

[0431]

[Chemical 148]

To ester 19 (956 mg) was added CH ₂ Cl ₂ (4 mL) followed by TFA.
(4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the product was triturated with ether to give acid 21 (802 mg) as a white solid.

[0433]   Production of Example 22

[0434]

[Chemical 149]

Nitrile 17 (330 mg, 0.02 mL) in EtOH / H ₂ O (18 mL, 2: 1).
To 76 mmol), hydroxylamine (189 mg, 2.72 mmol) was added, followed by K ₂ CO ₃ (209 mg, 1.5 mmol). The reaction mixture was heated to 65 ° C. overnight. The solvent was then removed under reduced pressure. The residue is water and E
Sorted to tOA. The organic phase is washed with brine, dried over MgSO ₄ , filtered and
And concentrated. The product was then triturated with ether to give 22 (276 mg) as a white solid.

[0436]   Production of Example 23

[0437]

[Chemical 150]

Glyoxamide 22 (100 mg, 0.21 mmol) was added to toluene (1.5 m
L) was added, followed by K ₂ CO ₃ (35 mg, 0.26 mmol) and phosgene in toluene (1.09 ml, 20% solution). The reaction mixture was heated at reflux for 2.5 hours. The mixture was then cooled to room temperature and stirred overnight. The product was filtered, concentrated and triturated with ether to give 23 (89 mg) as a golden solid.

[0439]

[Table 40]

[0440]

[Table 41]

[0441]

[Table 42]

[0442]   General manufacturing method for Examples 35-36.

[0443]

[Chemical 151]

Indole-3-glyoxylyl chloride I (3 g in CH ₂ Cl ₂ at room temperature
, 14.45 mmol) with tert-butyl 1-piperazinecarboxylate (2.7
g, 14.45 mmol) and diisopropylethylamine (2.76 ml, 1
5.9 mmol) was added. The light brown solution was stirred at room temperature for 2 hours, after which LC / MS analysis showed the reaction was complete. The solvent was removed under reduced pressure,
The resulting residue was diluted with ethyl acetate (25 ml) and diethyl ether (250 ml). Then, the organic solution was added to water (100 ml × 3) and brine (50 ml).
Washed with, dried over MgSO ₄ , filtered and concentrated. CH ₂ C on light yellow solid
It was added 30ml of 20% trifluoroacetic acid in l _2. The solution was concentrated and the pale brown solid was dried under reduced pressure to give 3.5 g (95%) of product II. LC
/ MS analysis showed the product to be 100% pure. This product was then used in the next reaction without further purification.

[0445]

[Chemical 152]

Substituted benzoyl chloride (3 eq) was added to piperazin glyoxamide II (1 eq) in dichloroethane (DCE), followed by i-Pr ₂ NEt (4 eq).
Was added. The reaction mixture is stirred at room temperature for 16 hours and the product III is conditioned HP
Purified by LC.

[0447]   General method for making Examples 35-56.

[0448]

[Chemical 153]

To indole gloxamide VI6 (1 eq) in DCE was added the substituted acid chloride (3 eq) followed by i-Pr ₂ NEt (4 eq). Reaction mixture at room temperature 1
Stir for 6 hours and purify the product VIIa by preparative HPLC.

[0450]

[Table 43]

[0451]

[Table 44]

[0452]   General manufacturing method for Examples 57-64.

[0453]

[Chemical 154]

Indole gloxamide (1 eq) in DCE with chloroformate R ₂ OCO
Cl (3 eq) was added, followed by i-Pr ₂ NEt (4 eq). The reaction mixture was stirred at room temperature for 16 hours and the carbamate VIIb was purified by preparative HPLC.

[0455]

[Table 45]

[0456]   General method for making Examples 65-69.

[0457]

[Chemical 155]

To the indole gloxamide VIe (1 eq) in NMP was added the carbamoyl chloride R ₁ R ₂ NCOCl ₂ (2 eq) followed by i-Pr ₂ NEt (4 eq).
Was added. The reaction mixture is stirred at room temperature and then urea VIIe is conditioned by HPLC.
Purified in.

[0459]   General method for making Examples 65-69.

[0460]

[Chemical 156]

To indole cloxamide (1 eq) in DCE was added P-nitrophenyl chloroformate (1.1 eq) followed by i-Pr ₂ NEt (3 eq).
The reaction mixture was stirred at room temperature for 3 hours and the crude was used in the next step without further treatment or purification.

[0462]

[Chemical 157]

To the crude P-nitrophenyl carbamate VIIIe was added the secondary amine R ₁ R ₂ NH. The reaction mixture was stirred at room temperature for 16 hours, then adjusted to urea IXe.
Purified by PLC.

[0464]   One manufacture of Examples 65-69 in Table 17.

[0465]

[Chemical 158]

To indole glyoxamide VIIe (1 eq) in CH ₂ Cl ₂ at room temperature was added isocyanate (R ₁ NCO) (2 eq) followed by i-Pr ₂ NEt (3 eq). The reaction mixture was stirred at room temperature, and the crude product Xe was adjusted to HP
Purified by LC.

[0467]

[Table 46]

[0468]   Production of Examples 70-71 in Table 18.

[0469]

[Chemical 159]

To the indole gloxamide XIf (1 eq) in DCE was added P sulfonyl chloride (2 eq) followed by i-Pr ₂ NEt (3 eq). The reaction mixture was stirred at room temperature for 3 hours and the crude product XIIf was purified by preparative HPLC.

[0471]

[Table 47]

[0472]   Additional analytical data for selected compounds

[0473]

[Chemical 160]

¹ H-NMR (300 MHz, DMF-d7): δ 8.30 (s, 1 H), 8.
22 (d, 1H, J = 7.26 Hz), 7.84 (d, 1H, J = 7.26H)
z), 7.30-7.54 (m, 7H), 4.99 (s, 3H), 3.52-3.
． 92 (m, 8H).

[0475]

[Chemical 161]

¹ H-NMR (300 MHz, CD3OD): δ8.28 (d, 1H, J = 8.
37 Hz), 8.22 (s, 1H), 7.64 (d, 1H, J = 7.26), 7
． 27-7.56 (m, 7H), 5.16 (d, 2H, J = 2.52Hz), 3
． 36-4.02 (m, 8H), 3.02 (t, 1H, J = 2.55Hz).

[0477]

[Chemical 162]

¹ H-NMR (500 MHz, CD ₃ Cl): δ 8.05 (s, 1 H), 7.4
5 (br.s, 5H), 6.88-7.01 (m, 2H), 5.04 (s, 2H)
), 3.79 (br.m, 4H), 3.59 (br.m, 4H). Analysis calculated values for _{C 23 H 18 F 2 N 4} O 3: C 63.30; H 4.1
6; N 12.84; F 8.71; O 11.00. Found C 62.33;
H 4.52; N 12.05. MS 437 (M + H) ⁺

[0479]

[Chemical formula 163]

¹ H-NMR (500 MHz, CD ₃ Cl): δ 7.99 (s, 1 H), 7.4
4 (br.s, 5H), 6.74-6.85 (m, 2H), 4.90 (s, 2H)
), 3.79 (br.m, 4H), 3.57 (br.m, 4H), 3.45 (q
, J = 11.4 Hz, 4H), 1.35 (t, J = 11.4 Hz, 3H),
1.21 (t, J = 11.4 Hz, 3H). Analysis calculated values for _{C 27 H 28 F 2 N 4} O 4: C 63.52; H 5.5
4; N 10.97. Found C 62.75; H 5.54; N 10.80.

[0481]

[Chemical 164]

¹ H-NMR (500 MHz, DMSO-d6): δ 8.32 (s, 1 H), 7
． 44 (br.s, 6H), 7.12 (app.t, 1H), 3.87 (s, 3)
H), 3.2-3.7 (br.m, 8H), analytical value calculated for MS 412 (M + H) ⁺ C ₂₂ H ₁₉ F ₂ N ₃ O ₃ : C 64.23; H 4.6.
5; N 10.1. Found C 64.58; H 4.74; N 9.63.

[0483]

[Chemical 165]

¹ H-NMR (500 MHz, DMSO-d6): δ 8.40 (s, 1 H), 7
． 44 (br.s, 6H), 7.14 (app.t, 1H), 5.01 (br.
s, 2H), 3.2-3.7 (br.m). Calculated for MS 470 (M + H) ⁺ C ₂₃ H ₂₁ F ₂ N ₅ O ₄ : C 58.85; H 4.5.
1; N 14.92. Found C 58.17; H 5.06; N 13.85.

[0485]

[Chemical 166]

¹ H-NMR (500 MHz, DMSO-d6): δ 8.40 (s, 1 H), 7
． 4-7.55 (m, 6H), 7.16 (app.t, 1H), 5.61 (br
． s, 2H), 3.2-3.7 (br.m). MS 496 (M + H) ⁺

The compositions of the present invention are orally, parenterally (subcutaneous injection, intravenous injection, in the form of dosage unit formulations containing a non-toxic pharmaceutically acceptable carrier, an adjuvant and a vehicle).
It can be administered by inhalation spray or rectally (including intramuscular, intrasternal injection or infusion techniques).

Accordingly, in accordance with the present invention, there are provided methods of treating HIV infections and viral infections such as AIDS, and pharmaceutical compositions. This treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention.

The pharmaceutical compositions may be in the form of orally administrable suspensions, tablets, nasal sprays, sterile injectable preparations, for example sterile injectable aqueous or oleaginous suspensions or suppositories.

When administered orally in suspension, these compositions are prepared according to techniques well known in the pharmaceutical formulation arts to give bulk, microcrystalline cellulose, alginic acid or sodium alginate as a suspending agent, a viscosity enhancing agent. May include methylcellulose as well as the well known sweeteners / flavors. As immediate release tablets, these compositions include microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other known excipients, binders, fillers, disintegrants, diluents and lubricants. Agents may be included.

Injectable solutions or suspensions are suitable non-toxic parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic solutions. Formulation according to well-known techniques by using sodium chloride solution, or a suitable dispersing or wetting and suspending agent, for example, a synthetic monone, a sterile, non-irritating, non-volatile oil containing diglyceride, and a fatty acid containing oleic acid. Can be transformed.

The compounds of the present invention may be administered orally to humans in a dosage range of 1-100 mg / kg body weight individually. One preferred dose is 1-10 mg / kg body weight for each individual dose. Another preferred dosage range is 1 to 20 mg / kg body weight orally for each administration. However, the particular dose level and number of doses for any individual patient may vary. And the activity of the specific compound to be used, metabolic stability and persistence of activity of the compound, age, body weight, general health, sex, diet, mood and time of administration, excretion rate, drug combination, specific conditions It will depend on a variety of factors, including treatment of the pain and host experience.

Abbreviations TFA Trifluoroacetic acid P-EDC Polymer supported 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDC 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide DCE 1,2-dichloroethane DMF N , N-dimethylformamide THF tetrahydrofuran NMP N-methylpyrrolidone BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 31/12 A61P 31/12 31/18 31/18 C07D 401/06 C07D 401/06 401/12 401 / 12 401/14 401/14 403/06 403/06 403/12 403/12 405/12 405/12 405/14 405/14 409/12 409/12 409/14 409/14 413/06 413/06 413 / 12 413/12 417/12 417/12 495/04 101 495/04 101 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, Z, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Fan, High Cannes, Connecticut, USA 06492 Warrinford Mallard Court 21 (72) Inventor Lin, Pin-Fan America United States Connecticut 06405 Branford Northford Road 169 (72) Inventor Spicer, Timothy P. Connecticut United States 06109 Weathersfeld Broad Street 108 (72) Inventor Wallas, Owen B. Connecticut United States 06443 Madison Lyle Drive 19 (72) Inventor One, Huy United States Connecticut 06457 Middletown Long Hill Road 837 A (72) Inventor One, Tao United States Connecticut 06457 Middletown Town Brook 1312 (72) Inventor Zan, Zonking United States Connecticut 06443 Madison Martelsham Heath Lane 14 (72) Inventor Yun, Cap-San Connecticut, USA 06457 Middletown Town Colony Drive 622 F Term (Reference) 4C063 AA01 AA03 BB03 BB07 B B08 CC34 CC51 CC58 CC62 CC67 CC75 CC76 CC92 CC94 DD06 DD22 DD34 EE01 4C071 AA01 BB01 CC22 DD04 EE13 FF23 GG03 JJ05 LL01 4C084 AA19 NA05 ZB33 ZC55 ZC75 GA08 GA08 MA02 GA02 BC04 GA12 BC02 GA02 BC08 NA05 NA14 ZB33 ZC55 4C204 BB01 CB03 DB16 EB02 FB01 GB01 GB03 GB17 GB24 GB25 GB40

Claims (13)

[Claims] 1. A compound of formula I or a pharmaceutically acceptable salt thereof: [Chemical 1]   Where R₁ , R₂ , R₃ , R_Four And R_Five Are independently H and C₁ -C₆ A
Rukiru, C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cyclo
Alkenyl, C₂ -C₆ Alkynyl, halogen, CN, nitro, COOR₆ Or
XR₇ And each of said alkyl and cycloalkyl is optionally 1-3 same
One or different halogen, amino, OH, CN or NO₂ May be replaced with;   R₆ Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl or benzyl
Each of said alkyl, cycloalkyl and benzyl is optionally 1-3
One or different halogen, amino, OH, CN or NO₂ May be replaced with;   X is O, S or NR₆ R₇ Is;   R₇ Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Al
Kenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Alkynyl or C (O) R₈
And each of said alkyl and cycloalkyl is optionally 1-3 identical or
Different halogen, OH, amino, CN or NO₂ May be replaced with;   R₈ Is H, C₁ -C₆ Alkyl or C₃ -C₆ Is cycloalkyl;   -W- is [Chemical 2] Is;   R₉ , R_Ten, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ , R_{twenty one}And R_{twenty two}Are independently H and C₁ -C₆ Alkyl, C₃ -C₆ Cycloa
Rukiru, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Al
Quinyl, CR_{twenty three}R_{twenty four}OR_{twenty five}, COR₂₆, COOR₂₇Or C (O) NR₂₈R₂₉And
Each of said alkyl and cycloalkyl is optionally 1-3 identical or different
Halogen, amino, OH, CN or NO₂ May be replaced with;   R_{twenty three}, R_{twenty four}, R_{twenty five}, R₂₆, R₂₇, R₂₈And R₂₉Are independently H and C₁ -C ₆  Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Shi
Chalkenyl or C₂ -C₆ Alkynyl;   Ar is a 4-7 membered aromatic ring, wherein the aromatic ring is O, S, N and NR.₆ Consists of
It may have 1-5 heteroatoms independently selected from the group, and if desired
B group may form a condensed ring;   B is phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, full
A group selected from the group consisting of oleenyl and anthracenyl; or 2-furyl, 3-
Furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyryl
Dil, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, iso
Oxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-
Triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pi
Razinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolidi
Nil, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo
[B] Furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimi
Dazolyl, benzthiazolyl, purinyl, 4H-quinolidinyl, quinolinyl, a
Soquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phena
Hetero selected from the group consisting of dinyl, phenothiazinyl and phenoxazinyl.
An aryl group;   B and the 4-7 membered aromatic ring are each independently R₃₀, R₃₁, R₃₂, R₃₃And R ₃₄ 1 to 5 substituents independently selected from   R_a And R_b Are independently H and C_1-6 Alkyl or phenyl;   Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pi
Radil, quinolyl, 3,5-dimethylisoxazolyl, isoxazolyl, 2
-Methylthiazolyl, thiazolyl, 2-thienyl, 3-thienyl or pyramidyl
Is;   P is 0-2;   R₃₀, R₃₁, R₃₂, R₃₃And R₃₄Are independently H and C₁ -C₆ Alkyl,
C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkeni
Le, C₂ -C₆ Alkynyl, halogen, CN, nitro, C (O) R₃₅, COXR ₃₆ , Hydroxy, COOR₆ , Hydroxymethyl, trifluoromethyl, trif
Luoromethoxy, O-[(C₁ -C_Four ) -Straight or branched alkyl], O-ben
Zil, O-phenyl, 1,2-methylenedioxy, OC (O) C_1-6 Alkyl,
SC (O) C₁ -C₆ Alkyl, S (O)_m C₁ -C₆ Alkyl, S (O)₂ N
R_a R_b , Amino, carboxy, OZ, CH₂ -(CH₂ )_p -Z, O (CH ₂  )_p -Z, (CH₂ )_p -O-Z, CH = CH-Z or XR₃₇And the al
Kill and cycloalkyl are optionally 1-3 identical or different halogen, amine
No, OH, CN or NO₂ May be replaced with;   m is 0-2;   R₃₅And R₃₆Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Is alkyl;   R₃₇Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Al
Kenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Alkynyl, C (O) R₃₈or
Is C (O) OR₃₉And each of said alkyl and cycloalkyl is optionally 1
-3 identical or different halogen, amino, OH, CN or NO₂ Replaced by
May be;   R₃₈And R₃₉Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Alkyl, wherein the alkyl and cycloalkyl are optionally 1-3 identical or
Are different halogens, amino, OH, CN or NO₂ May be replaced with
R₃₉Is not H;   R₄₀Is (CH₂ )_n -Y, where n is 0-6;   Y is selected from the following (1) and (2); (1) H, C₁ -C₆ Alkyl, C ₃  -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkenyl
, C₂ -C₆ Alkynyl, halogen, CN, nitro, Ar, COOR₆ , COO
Ar, CONR_a R_b , TR₆ , NR_a R_b , -NC (O) NR_a R_b , -OC
(O) R₆ , -C [N (R_a )₂ ] = N-T-R_b , XR₆ , -C (O) R₆ ,
-C (O) Ar, -S (O) R_a Or -S (O)₂ R_a Where Y is -S (
O) R_a Or -S (O)₂ R_a When is R_a Is not H; and (2) O, S
, SO, SO₂ , N and NR₄₁A 1-3 membered heterocyclic group selected from the group consisting of:
The heterocyclic group is optionally R₆ R may be substituted with_Four Is hydrogen, (C₁ -C_Four
) -Straight or branched alkyl, (C₂ -C_Four ) -Straight or branched alkenyl or
Selected from the group consisting of alkynyl;   T is S or O;   However, R₁ -R_Five , R₉ -R₁₆And R₃₀-R₃₄But at the same time not all hydrogen
And Ar is phenyl;   Also R₁ -R_Five , R₉ -R₁₆And R₃₀-R₃₄But at the same time not all hydrogen
And Ar is 2-furyl. 2. The compound of claim 1 wherein Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, pyrazinyl, thiazolyl, imidazolyl or thiadiazolyl. 3. W is [Chemical 3] And   R₉ , R_Ten, R₁₁, R₁₂, R₁₃, R₁₄And R₁₅Are each H, and R ₁₆ The compound of claim 1, wherein is methyl. 4. The compound according to claim 1, wherein R ₂ is H, fluorine or methoxy. 5. The compound according to claim ₁ , wherein R ₁ , R ₃ and R ₄ are each H. 6. A medical preparation containing an antivirally effective amount of the compound according to any one of claims 1-5. 7. An antiviral effective amount of an AIDS therapeutic agent selected from the group consisting of (a) AIDS antiviral agent, (b) antiinflammatory agent, (c) immunomodulator and (d) HIV entry inhibitor. The formulation of claim 6 which is effective in treating HIV infection. 8. An anti-drug compound of formula II or a pharmaceutically acceptable salt thereof.
Including a virus-infected person characterized in that an effective dose of Ils is administered to a mammal.
Treatment methods for mammals: [Chemical 4]   Where R₁ , R₂ , R₃ , R_Four And R_Five Are independently H and C₁ -C₆ A
Rukiru, C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cyclo
Alkenyl, C₂ -C₆ Alkynyl, halogen, CN, nitro, COOR₆ Or
XR₇ And each of said alkyl and cycloalkyl is optionally 1-3 same
One or different halogen, amino, OH, CN or NO₂ May be replaced with;   R₆ Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl or benzyl
Each of said alkyl, cycloalkyl and benzyl is optionally 1-3
One or different halogen, amino, OH, CN or NO₂ May be replaced with;   X is O, S or NR₆ R₇ Is;   R₇ Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Al
Kenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Alkynyl or C (O) R₈
And each of said alkyl and cycloalkyl is optionally 1-3 identical or
Different halogen, OH, amino, CN or NO₂ May be replaced with;   R₈ Is H, C₁ -C₆ Alkyl or C₃ -C₆ Is cycloalkyl;   -W- is [Chemical 5] Is;   R₉ , R_Ten, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀ , R_{twenty one}And R_{twenty two}Are independently H and C₁ -C₆ Alkyl, C₃ -C₆ Cycloa
Rukiru, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Al
Quinyl, CR_{twenty three}R_{twenty four}OR_{twenty five}, COR₂₆, COOR₂₇Or C (O) NR₂₈R₂₉And
Each of said alkyl and cycloalkyl is optionally 1-3 identical or different
Halogen, amino, OH, CN or NO₂ May be replaced with;   R_{twenty three}, R_{twenty four}, R_{twenty five}, R₂₆, R₂₇, R₂₈And R₂₉Are independently H and C₁ -C ₆  Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Shi
Chalkenyl or C₂ -C₆ Alkynyl;   Ar is a 4-7 membered aromatic ring, wherein the aromatic ring is O, S, N and NR.₆ Consists of
It may have 1-5 heteroatoms independently selected from the group, and if desired
B group may form a condensed ring;   B is phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, full
A group selected from the group consisting of oleenyl and anthracenyl; or 2-furyl, 3-
Furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyryl
Dil, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, iso
Oxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-
Triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pi
Razinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolidi
Nil, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo
[B] Furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimi
Dazolyl, benzthiazolyl, purinyl, 4H-quinolidinyl, quinolinyl, a
Soquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phena
Hetero selected from the group consisting of dinyl, phenothiazinyl and phenoxazinyl.
An aryl group;   B and the 4-7 membered aromatic ring are each independently R₃₀, R₃₁, R₃₂, R₃₃And R ₃₄ 1 to 5 substituents independently selected from   R_a And R_b Are independently H and C_1-6 Alkyl or phenyl;   Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pi
Radil, quinolyl, 3,5-dimethylisoxazolyl, isoxazolyl, 2
-Methylthiazolyl, thiazolyl, 2-thienyl, 3-thienyl or pyramidyl
Is;   P is 0-2;   R₃₀, R₃₁, R₃₂, R₃₃And R₃₄Are independently H and C₁ -C₆ Alkyl,
C₃ -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkeni
Le, C₂ -C₆ Alkynyl, halogen, CN, nitro, C (O) R₃₅, COXR ₃₆ , Hydroxy, COOR₆ , Hydroxymethyl, trifluoromethyl, trif
Luoromethoxy, O-[(C₁ -C_Four ) -Straight or branched alkyl], O-ben
Zil, O-phenyl, 1,2-methylenedioxy, OC (O) C_1-6 Alkyl,
SC (O) C₁ -C₆ Alkyl, S (O)_m C₁ -C₆ Alkyl, S (O)₂ N
R_a R_b , Amino, carboxy, OZ, CH₂ -(CH₂ )_p -Z, O (CH ₂  )_p -Z, (CH₂ )_p -O-Z, CH = CH-Z or XR₃₇And the al
Kill and cycloalkyl are optionally 1-3 identical or different halogen, amine
No, OH, CN or NO₂ May be replaced with;   m is 0-2;   R₃₅And R₃₆Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Is alkyl;   R₃₇Is H, C₁ -C₆ Alkyl, C₃ -C₆ Cycloalkyl, C₂ -C₆ Al
Kenil, C₃ -C₆ Cycloalkenyl, C₂ -C₆ Alkynyl, C (O) R₃₈or
Is C (O) OR₃₉And each of said alkyl and cycloalkyl is optionally 1
-3 identical or different halogen, amino, OH, CN or NO₂ Replaced by
May be;   R₃₈And R₃₉Are independently H and C₁ -C₆ Alkyl or C₃ -C₆ Cyclo
Alkyl, wherein the alkyl and cycloalkyl are optionally 1-3 identical or
Are different halogens, amino, OH, CN or NO₂ May be replaced with
R₃₉Is not H;   R₄₀Is (CH₂ )_n -Y, where n is 0-6;   Y is selected from the following (1) and (2); (1) H, C₁ -C₆ Alkyl, C ₃  -C₆ Cycloalkyl, C₂ -C₆ Alkenyl, C₃ -C₆ Cycloalkenyl
, C₂ -C₆ Alkynyl, halogen, CN, nitro, Ar, COOR₆ , COO
Ar, CONR_a R_b , TR₆ , NR_a R_b , -NC (O) NR_a R_b , -OC
(O) R₆ , -C [N (R_a )₂ ] = N-T-R_b , XR₆ , -C (O) R₆ ,
-C (O) Ar, -S (O) R_a Or -S (O)₂ R_a Where Y is -S (
O) R_a Or -S (O)₂ R_a When is R_a Is not H; and (2) O, S
, SO, SO₂ , N and NR₄₁A 1-3 membered heterocyclic group selected from the group consisting of:
The heterocyclic group is optionally R₆ R may be substituted with_Four Is hydrogen, (C₁ -C_Four
) -Straight or branched alkyl, (C₂ -C_Four ) -Straight or branched alkenyl or
Selected from the group consisting of alkynyl;   T is S or O. 9. The method of claim 8, wherein the virus is HIV. 10. Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl,
9. The method of claim 8 which is pyrazinyl, thiazolyl, imidazolyl or thiadiazolyl. 11. W is Wherein _{R 9, R 10, R 11} , R 12, R 13, R 14 and R ₁₅ are each hydrogen; and The method of claim 8 R ₁₆ is a group represented in methyl. 12. The method of claim 8 wherein R ₂ is H, fluorine or methoxy. 13. The method of claim 8 wherein R ₁ , R ₃ and R ₄ are each H.